Human Molecular Genetics, 2002, Vol. 11, No. 10 1195-1206
© 2002 Oxford University Press
Genetic modifiers of vision and hearing
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609-1500, USA
Received February 22, 2002; Accepted February 27, 2002
 |
ABSTRACT |
|---|
 TOP ABSTRACT PRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...PRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...STRATEGIES FOR CLONING MODIFIER...SUMMARY/PERSPECTIVESREFERENCES |
|---|
The identification of ‘disease genes’ and the mutations within them has greatly enhanced our understanding of normal function in the eye and ear. At the same time, it has become clear that these single-gene mutations must reside in a permissive genetic background for a disease phenotype to manifest. Segregating background genes can also modify the age of onset, rate of progression or severity of these diseases. These background genes that interact with the disease mutation and that are responsible for the specific phenotypes observed are commonly called genetic modifiers. Identification of these modifier genes may define the biological pathways that lead from the primary genetic defect to the aberrant phenotype. Once the identities of modifier genes that suppress vision or hearing loss become known, the door opens to new potential therapeutic targets, since these modifier genes may be more amenable to treatment than the primary mutant gene.
More often than not, a given genetic disorder may manifest in a variety of ways. Variable disease phenotypes result from alternate alleles (allelic heterogeneity), environmental influences, genetic modifier loci, or a combination of these factors. While there have been many examples of allelic heterogeneity and environmental factors that influence the outcome of genetic mutations (1–5), this review focuses on genetic modifiers. Modifier genes can affect the phenotypic outcome of a given genotype by interacting in the same or a parallel biological pathway as a ‘disease gene’. The effect can be enhancing, leading to a more severe mutant phenotype, or suppressive, reducing the mutant phenotype even to the extent of completely restoring the normal condition (Fig. 1). Modifier genes can also alter the pleiotropy of a given disease, resulting in different combinations of traits. In addition, for any given disorder, multiple modifier genes may act in combination to create a final, cumulative effect on the expression of a phenotype.
|
The study and identification of genetic modifier loci promises new insights into the biological pathways in which Mendelian disease genes act and through which they cause disease. For example, knowing the molecular basis of a genetic modifier may help in better diagnosis and treatment of disease, perhaps by defining a particular subgroup within the disease population. In addition, the identification of modifier genes may lead to new treatments – either by providing additional information about genetic contributions to the phenotype for which treatment may already be available or by pointing to additional steps in a biological pathway that may be more amenable to treatment.
Although examples of modifier genes in human studies are not abundant, many genetic modifiers affecting phenotypic presentation of vision or hearing disorders in mice have been reported (6) (http://www3.ncbi.nlm.nih.gov/Omim/: http://www.sph.uth.tmc.edu/Retnet/disease.htm:). This review will focus on the evidence for modifier genes that specifically affect ocular and hearing disease phenotypes in humans as well as those reported in mice that have recently been described in the literature.
|
PRIMARY MUTATIONS KNOWN TO AFFECT VISION |
|---|
|
TOPABSTRACTPRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...PRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...STRATEGIES FOR CLONING MODIFIER...SUMMARY/PERSPECTIVESREFERENCES |
|---|
The visual process involves a complex set of physicochemical reactions that convert light energy into neuronal signals that transmit information to the brain (Fig. 2). The anterior part of the eye (including lens, cornea, pupil, iris and ciliary body) is responsible for maintaining optimal conditions for light to enter the eye. This involves providing a clear, well-nourished, surface with proper supporting tissue for the cornea and lens to refract the right amount of light onto the retina without any interference. The posterior portion of the eye (the retina and optic nerve) is required for the conversion of light energy into chemical and electrical stimuli and subsequent transmission of the sensory neural signals to the visual cortex of the brain. Absorption of light causes a structural change in chromophores in the photoreceptor cell that through a signaling cascade causes membrane hyperpolarization and changes in neurotransmitter release at the photoreceptor/bipolar cell synapse. The signal is then transmitted by neuronal cells (bipolar and ganglion cells) through the optic nerve to the visual cortex in the brain. Defects in any portion of the eye can disrupt the visual process, affecting visual acuity as well as discrimination of texture, color, depth and motion. Many of the genes involved in the visual cascade have been identified in recent years. At present, almost 300 genes are associated with ocular disease; over 200 of these genes cause retinal disorders that affect the visual cascade and retinal development, and approximately 50 genes are associated with anterior eye defects (Table 1) (http://www3.ncbi.nlm.nih.gov/Omim/: http://www.sph.uth.tmc.edu/Retnet/disease.htm:). Additional ocular diseases have been associated with particular chromosomal regions, but the underlying genes remain to be identified (http://www.sph.uth.tmc.edu/Retnet/disease.htm: http://genetics.med.harvard.edu/~cepko/SAGE/).
|
|
|
EVIDENCE FOR MODIFIERS OF OCULAR DISEASES IN HUMANS |
|---|
|
TOPABSTRACTPRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...PRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...STRATEGIES FOR CLONING MODIFIER...SUMMARY/PERSPECTIVESREFERENCES |
|---|
Phenotypic variation has been reported for many of the described primary ocular diseases, indicating the potential presence of genetic modifiers. An early, classic example suggesting modifier effects is the report of a nuclear family in which different members carrying the same deletion in their RDS gene develop retinitis pigmentosa (RP), pattern dystrophy or fundus flavimaculatus (7). Although the genes underlying the above modifications have yet to be identified, one gene that is known to interact with RDS is ROM1. Individuals heterozygous for a Leu185Pro allele of peripherin/RDS plus an additional mutation within ROM1 present with reduced electroretinographic amplitudes typical of RP (8). Three more recent publications involving the retinitis pigmentosa 1 (RP1), primary open-angle glaucoma (POAG) and Bardet–Biedl syndrome (BBS) genes also suggest genetic modifiers effects. In a recent study of 1941 probands with a clinical diagnosis of retinitis pigmentosa, 17 patients were shown to harbor mutations within their RP1 gene (9). The most common mutation found was a premature stop codon, Arg677Ter. Clinical characterization of 22 patients from 10 pedigrees (11 patients were from the same pedigree) demonstrated variability in the severity of visual field loss both within and among families. The authors suggested a role for both modifier genes and environmental influences in the regulation of this variability.
Evidence of phenotypic modifiers has also been reported in patients with POAG who have mutations within their myocilin (MYOC) gene. In a population study of 1730 probands, the most frequent mutation, Gln368Ter, was associated with adult-onset POAG and elevated intraocular pressure. Haplotype analysis among individuals with the Gln368Ter mutation suggested a founder effect or common ancestor. Despite this, patients with this particular mutation showed variation both in age of onset and in disease severity, which ranged from ocular hypertension to legal blindness with severe visual field loss (10).
Finally, a recent report identifies mutations in more than one gene in individuals with BBS, a pleiotropic disorder with many clinical features, including pigmentary retinopathy. The disease is genetically heterogeneous and is inherited in an autosomal recessive manner, but variability in phenotypic expressivity of BBS is well documented (11,12). Several of the BBS genes have recently been identified (13–17). It has been postulated that the genes at independent BBS loci could interact in a common pathway. One particular finding (17) notes the presence of homozygosity for a mutation at the BBS6 locus and simultaneously the presence of heterozygosity for another mutation at a second BBS locus. The authors term the inheritance ‘triallelic’, suggesting a mode of disease transmission requiring mutations in genes at two independent loci in order for the disease to manifest. One way in which the data of the three mutant BBS alleles have been interpreted is that the disease is inherited in a recessive manner with one of the genes serving as a modifier of penetrance (18). The third BBS allele identified in the report by Katsanis et al. (17) may represent such a gene, in accord with the definition of modifiers as genes at independent loci, that interact with the primary disease gene to alter the phenotype.
The degree to which a phenotype is altered by modifiers and the method by which the alteration occurs is uncharted territory. Discoveries like those described above are intriguing. Study of diseases such as BBS with complex inheritance patterns will greatly aid in elucidating the variety of gene–gene interactions that occur in ocular diseases.
|
EVIDENCE FOR MODIFIERS OF OCULAR DISEASES IN MICE |
|---|
|
TOPABSTRACTPRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...PRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...STRATEGIES FOR CLONING MODIFIER...SUMMARY/PERSPECTIVESREFERENCES |
|---|
In mice, the existence of modifier genes was originally postulated from the variation in phenotype observed when spontaneous mutations were transferred to different inbred backgrounds through construction of congenic lines (19). More recently variations in phenotypic expression have become evident as targeted mutation models, originally propagated in stem cells derived from the inbred strain 129, were made chimeric with the C57BL/6 strain and subsequently crossed to C57BL/6 (B6). The initial targeted mutant phenotypes determined on the mixed 129/B6 background often have been reported to change as the line is made congenic on the B6 background (20).
Mouse models with ocular diseases in which phenotypic expression is affected by genetic background are shown in Table 2. Modifier effects can result from a single gene at an independent locus or from the combined effects of several genes, as is typical of quantitative trait loci (QTL). Also, alleles of modifier genes in one strain may completely suppress the mutant phenotype, while alleles from another strain may enhance the phenotype, affecting severity and/or age of onset. Recent examples of genetic modifiers for various ocular disorders are described below.
|
Mutants with ocular disorders caused by mutations within genes controlling transcriptional regulation during eye development exhibit variable phenotypic expressivity in fully inbred strains, in addition to modification of penetrance of these disease phenotypes when placed in different genetic backgrounds. The variable phenotypic expressivity observed in these mutants on fully inbred backgrounds is more likely to be due to developmental timing events that are environmentally influenced than by genetic predisposition (21). Conversely, a reduction in penetrance of the disease phenotypes that is observed when a mutant is propagated in a different mouse strain is probably genetically influenced. For example, in examining the mutant congenital hydrocephalus (ch), which is caused by a mutation in the forkhead boxC1 transcription factor gene (Foxc1) (22), numerous defects in the anterior segment were observed in ch/+ mice on the CHMU/Le inbred background (23). Phenotypes such as displaced and irregularly shaped pupils that were observed in most mutant mice were present either bilaterally or unilaterally. Some of the mice exhibited prominent Schwalbe's line (posterior embryotoxon), corneal opacity, anterior synechia ranging in size from a broad sheath to threadlike strands, thinning of the iris stroma, and cataracts. When the ch/+ mutation was propagated in the Mus musculus castaneus (CAST) background, there was a significant reduction in the penetrance of particular phenotypes (23). Another example of strain-specific genetic modifiers with anterior segment defects is observed in mice with haploinsufficiency of bone morphogenic protein 4 (BMP4) (24). In this case, the most severe phenotypes were seen on the C57BL/6J background. Anterior segment defects varying from relatively normal eyes to severe abnormalities affecting size and shape of pupils, displaced Schwalbe's line, corneal thinning and opacity of the cornea were observed in B6 and, to a lesser extent, in strain 129/Sv (24). Finally, the murine ocular retardation (or J) mutation in the homeobox gene Chx10 results in blindness due to severe microphthalmia, thin, poorly laminated retina with missing bipolar cells, and lack of optic nerve in strain 129/Sv (25). When the or J mutation was placed on the CAST background, the phenotype was less severe (26). Under the influence of castaneus genes, mice homozygous for the or J-mutation varied in eye size phenotype from a slight diminution to nearly normal eye size. Retinal organization, although not normal, was greatly improved on the CAST background, with the presence of bipolar cells and improved lamination. The modifier genes did not completely suppress the Chx10or-J mutation phenotype, since mice still showed incomplete growth and lack of cell differentiation in the periphery of the retina. Several modifier loci appear to contribute to the phenotypic expression of Chx10or-J in CAST mice. Identification of these modifiers, while important in defining pathways important in eye development, may be more difficult because of the variability in disease presentation and the possibility that different modifier genes regulate specific phenotypic characteristics. Therefore, phenotypes must be carefully defined both spatially and temporally. Genetic complexity may also be reduced by dividing the disease characteristics into subphenotypes.
The recently reported novel recessive congenital cataract mutant, RCT (27), is an example in which careful phenotypic characterization led to the chromosomal mapping of two loci, one which was essential for the disease phenotype (rct) while the other accelerated the disease (modifier of rct, mrct). Investigators observed three classes of mice in a backcross: with normal lens, with early-onset cataracts that could be detected visually and with late-onset cataracts that could only be detected histologically. Linkage analysis revealed that the rct gene is linked to mouse chromosome 4 and that mrct is linked to chromosome 5.
Genetic background can also dictate the survival of the neural retina despite the presence of a primary mutation that normally leads to retinal cell death. For example mice homozygous for a targeted mutation of Rho appear to be protected by modifiers on a C57BL/6J genetic background when compared with the 129Sv background (28). Mice carrying the Rho-/- mutation on the C57BL/6J background have greater cone photoreceptor function and number of photoreceptor nuclei. A demonstration of the complexity of genetic background interactions was an intercross between C57BL/6J–tub/tub and AKR/J–+/+F2 progeny, in which survival of photoreceptors was examined (29). At 20 weeks of age, C57BL/6 mice harboring a mutation within the tub gene normally only have 5–10% of residual outer nuclear layer (ONL) thickness remaining while the ONL thickness in F2 mice from the above intercross ranged from 5% to 80%. One QTL on chromosome 11, modifier of tubby retinal degeneration 1 (motr1), was detected with high statistical significance in a genome-wide scan, and two additional loci on chromosomes 2 and 8 showed suggestive linkage. Interestingly, protective alleles came from both the resistant AKR (motr1 and the chromosome 2 locus) as well as the susceptible B6 backgrounds (the chromosome 8 locus). Identification of these and other modifier loci will provide better insight into pathways involved in primary mutant gene function and also in degeneration.
|
PRIMARY MUTATIONS KNOWN TO AFFECT HEARING |
|---|
|
TOPABSTRACTPRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...PRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...STRATEGIES FOR CLONING MODIFIER...SUMMARY/PERSPECTIVESREFERENCES |
|---|
The hair cells of the inner ear have evolved uniquely to convert sound into a neuronal signal. A sound wave reaches the basilar membrane in the organ of Corti as a hydromechanical stimulus and is then converted to a wave movement of this structure (Fig. 3). This basilar-membrane movement causes hair cell stereocilia to be deflected by the tectorial membrane. The very slight movement of sterocilia triggers the hearing process by mechanically opening gated ion channels. This allows an influx of potassium that causes depolarization of the hair cells' membrane potential, and finally results in transmission of electrical signals to the central nervous system, primarily through synaptic junctions between the hair cells and spiral ganglion cells. Over the past several years, many mutations causing hearing impairment have been identified in humans and mice (Table 3)(6,30,31). Identification of phenotypic features and a molecular basis for these mutations has led to a remarkable understanding of the hearing process in the inner ear (reviewed in 31). Technical advances such as the availability of whole genome sequences of human and mouse will accelerate the discovery of genes responsible for hearing loss and the modifiers described below.
|
|
|
EVIDENCE FOR MODIFIERS OF HEARING IMPAIRMENT IN HUMANS |
|---|
|
TOPABSTRACTPRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...PRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...STRATEGIES FOR CLONING MODIFIER...SUMMARY/PERSPECTIVESREFERENCES |
|---|
As with many disorders of the eye, phenotypic variation in heritable forms of hearing impairment have been reported both within families (32–34) and in individual probands carrying the same genetic mutations (35). Recently, two human modifiers of hearing have been reported. The DFNM1 locus completely suppresses hearing loss among individuals homozygous for a DFNB26 mutation (33). In this rare instance, incomplete penetrance of the disease phenotype was observed in seven family members homozygous for DFNB26 mutations. The family size was sufficiently large to allow the investigators to map a single suppressive locus to chromosome 1q24. Bykhovskaya et al. (36) provide another example in which a locus on chromosome 8, near marker D8S277, modifies maternally inherited deafness associated with a mutation (A1555G) in the mitochondrial 12S ribosomal RNA.
|
EVIDENCE FOR MODIFIERS OF HEARING IMPAIRMENT IN MICE |
|---|
|
TOPABSTRACTPRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...PRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...STRATEGIES FOR CLONING MODIFIER...SUMMARY/PERSPECTIVESREFERENCES |
|---|
While the number of hearing modifiers reported in mice are fewer than those reported for ocular diseases, greater advances have been made in their molecular identification. Three examples of mouse modifiers, both qualitative and quantitative, that have been mapped and/or identified are described in detail below (Table 4). In each case, new insights have been gained into the pathway or function of the gene/mutation on which the modifier was epistatic.
|
Deaf waddler (dfw), a neuroepithelial deafness mutation that arose spontaneously on the C3H/HeJ inbred strain, was localized on chromosome 6 (37). A second allele of deaf waddler (dfw2J) was identified on the BALB/cBy genetic background (38). The gene responsible for the dfw mutation has been identified as a plasma membrane ATPase type 2-Ca2+ transporter pump (Atp2b2) (39). The protein ATP2B2, which localizes to stereocilia and the basolateral wall of hair cells, may be essential for removing Ca2+ from subcellular domains of both auditory and vestibular hair cells (39). Auditory brain stem response (ABR) tests of dfw2J/dfw2J mice at 3 weeks of age show complete hearing loss with no response to a 100 dB SPL stimulus (38). Heterozygous BALB/cBy-dfw2J/+ mice exhibit delayed hearing loss beginning at 4 weeks of age and progressing to complete deafness by 12 weeks of age (38). The appearance of hearing loss in dfw/+ mice is dependent on the genetic background (38). A CAST allele of a modifier gene protects dfw/+ mice from hearing loss in a dominant fashion, whereas the BALB/cBy allele permits hearing loss to occur. A genome-wide scan revealed significant linkage on chromosome 10. This locus was named modifier of deaf waddler (mdfw). Several loci associated with hearing function map near the mdfw locus, including the mouse mutations waltzer and Jackson circler (39). In humans, the non-syndromic hearing loss locus DFNB12 and the Usher syndrome type 1D gene have been mapped to chromosome 10q21, which is homologous to the mdfw region in the mouse. Also, in mice, an age-related hearing loss locus (Ahl) was identified by QTL analysis on mouse chromosome 10, overlapping with the mdfw region (40). Based on map location and the fact that susceptible alleles of both Ahl and mdfw were contributed by the same strains, it was hypothesized that the two loci represent the same gene (38,40, 41). Recently, mutations within cadherin 23 (Cdh23) were identified as responsible for the waltzer mutant and for human Usher type ID. Subsequently, Bryda et al. (42) reported a high-resolution genetic and physical map (500 kb) of the mdfw and waltzer regions and suggested that mdfw and Cdh23v are allelic. Because cadherins require calcium for their function, Cdh23 is an attractive candidate for the mdfw locus. Although experiments are necessary to prove that allelic differences in Cdh23 are responsible for mdfw, identification of the modifier has provided an additional entry point into understanding the interaction of mdfw with the ATPase type 2-Ca2+ pump encoded by dfw.
In the second example, mutations in the neuronal tub gene are known to cause obesity, retinal degeneration, and hearing loss in tubby mice. Several potential functions of the Tub protein have been suggested, including vesicular trafficking, mediation of insulin signaling and gene transcription. However, the context and complete pathways through which Tub functions in neurons remain to be elucidated. All the phenotypes that tubby mice exhibit are affected by genetic background (29,43). The profound early hearing loss in B6-tub/tub mice is completely rescued in tub/tub homozygous F2 progeny derived from crossing B6-tub/tub mice with mice of strains AKR/J, CAST/Ei and 129P2/Ola. Linkage analysis identified a major modifier locus, modifier of tubby hearing 1 (moth1) on chromosome 2 (43). A single moth1 allele from any of several different inbred strains protects tubby mice from the hearing loss associated with a B6-derived recessive moth1 allele. Recently, the microtubule-associated protein 1A gene (Mtap1a) has been identified as the moth1 gene (44). There are 10 amino acid alterations and an alanine–proline repeat length difference between the Mtap1 alleles of B6 and protective strains. Microtubule-associated proteins were originally shown to stabilize microtubules. The MTAP1A protein has also been suggested to play a role in the trafficking of synaptic components from the cytosol to the synaptic junction (45,46). Since the amino acid changes observed in MTAP1A affect the binding of MTAP1A to PSD95, which is a major component of the synaptic cytoarchitecture, a potential difference among strains in the capacity to transport synaptic components was suggested. Therefore, it has been hypothesized that the function of Tub is associated with synaptic function or structure.
Genetic modifiers do not need to be genes residing in the autosomal and sex chromosomes. Recently Johnson et al. (47) demonstrated the first mouse model with a naturally occurring mtDNA mutation affecting the age-related hearing loss locus, Ahl. To assess the potential mitochondrial effect on Ahl, reciprocal matings were made between males and females from three hearing-impaired inbred mice strains, A/J, NOD/LtJ and SKH2/J, and the normally hearing CAST/Ei. The authors found a maternal effect on AHL in N2 mice from the (A/J x CAST/Ei)F1 x A/J and the reciprocal backcross. There was a significant difference in hearing loss between mice carrying two copies of the A/J Ahl allele combined with mitochondria originating from A/J versus mitochondria inherited from CAST/Ei. An adenine insertion in the mitochondrial arginine tRNA (mt-Tr) gene of the A/J strain is thought to be responsible for the phenotypic difference.
|
STRATEGIES FOR CLONING MODIFIER GENES |
|---|
|
TOPABSTRACTPRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...PRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...STRATEGIES FOR CLONING MODIFIER...SUMMARY/PERSPECTIVESREFERENCES |
|---|
A major stumbling block for the identification of modifiers in humans is the ability to map these loci in the face of large genetic heterogeneity in the human population. While chromosomal localization of modifier loci in some extended human families may be feasible, moving from a map position to a region narrow enough to enable physical mapping and gene identification will be difficult.
The most efficient mapping approach for modifier genes in mouse is to cross parental inbred strains that carry the disease-causing mutation and exhibit a difference in phenotype. An example (Fig. 1) shows B6-tub/tub mice with retinal degeneration, whereas some F2 AKR;B6-tub/tub mice are protected and have almost normal photoreceptor cell layer thickness. When the F1 progeny of these two strains are intercrossed, the modifier genes segregate in the F2 population. Since a modifier gene by itself does not usually produce a phenotype, only the F2 animals that are homozygous for the primary disease-causing mutation (recessive disease) will show phenotypic variation. Standard QTL analysis methods can be used to map the modifier loci in F2 animals (29,48).
Identification of the vision and hearing genetic modifiers for which chromosomal locations have been mapped may also be challenging, especially if more than one gene is contributing to modify the phenotype. If a major modifying locus is found (explaining the majority of the phenotypic variance), then conventional fine mapping in a large F2 intercross combined with progeny testing can sufficiently narrow the genetic interval to allow one to proceed with positional cloning (43,44). When multiple loci contribute smaller proportions of the phenotypic variance, congenic lines may need to be constructed to isolate the modifier loci. If the phenotypic effect of the modifier locus in the congenic line is greater than the non-genetic variation, the line can be used in crosses for fine-resolution mapping, as in the case of the major modifier (Fig. 4). Conventional positional cloning techniques may be applied once a high-resolution map has been obtained (48,49). Our ability to identify modifier genes may be enhanced by the combined use of congenic lines and gene expression microarray analysis, which may directly identify a misregulated modifier allele or point to the misregulation of a pathway in which the modifier gene plays a role.
|
|
SUMMARY/PERSPECTIVES |
|---|
|
TOPABSTRACTPRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...PRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...STRATEGIES FOR CLONING MODIFIER...SUMMARY/PERSPECTIVESREFERENCES |
|---|
Genetic modifiers clearly play a role in the phenotypic variation observed in both genetic disorders of vision and hearing. They have been shown to affect the age of onset, the degree of severity, the rate of disease progression, and the presence or absence of a particular disease phenotype.
While some modifier effects have been localized to a chromosome, cloning of modifier genes may prove to be a difficult task. In humans, this is in part due to genetic heterogeneity both in terms of possible disease genes (locus heterogeneity) and in the form of haplotypes on which disease mutations arose (allelic heterogeneity). Some phenotypic modifications may also be the result of the interaction of several genes that modulate a disease phenotype. Unless there is a significant contribution from one locus, they may be difficult to isolate. The paradigm of studying disease modifiers in mouse and determining if those modifiers play a similar role in humans may be the most efficient method for identification of modifiers. Availability of the complete human and mouse genome sequences (http://www.ncbi.nlm.nih.gov/, http://public.celera.com/cds/login.cfm, http://mouse.ensembl.org/Mus_musculus/) will greatly aid in this quest. Advances in annotating the genomic sequences will be aided by the availability of expressed sequence tags from specific cell types in the eye (retina) and ear (cochlea). This information helps to prioritize candidates in the vicinity of mapped modifier genes. Large-scale gene expression analysis with microarrays made from these specialized cDNA libraries may identify genes that are co-regulated by the modifiers and help define pathways. Taken together, the rate at which modifiers are identified is expected to increase in the near future.
The modifiers that have been identified to date have provided additional information about pathways in which the primary mutation functions as well as new entry points for understanding the pathological effects of the disease genes. Finally, although currently unsubstantiated, one might imagine that the elucidation of modifier genes associated with the suppression of ocular and hearing defects may be useful in designing new therapeutics that target enhanced expression of modifiers in affected patients, improving prediction of risk factors for susceptibility, and eventual prevention of disease manifestation.
|
ACKNOWLEDGEMENTS |
|---|
We thank Drs Richard S. Smith, Barbara B. Knowles, Kenneth R. Johnson, and Luther Young for carefully reviewing this manuscript. This study was supported by the following grants: the National Eye Institute (EY11996, EY12093, F32-EY07080), Foundation Fighting Blindness, Macular Vision Research Foundation, National Institute of Diabetes and Digestive and Kidney Diseases (DK59601), AXYS Pharmaceuticals Inc. Institutional shared services were supported by National Cancer Institute Cancer Center Grant CA-34196.
|
FOOTNOTES |
|---|
* To whom correspondence should be addressed. Tel: +1 207 288 6383; Fax: +1 207 288 6077; Email: pmn@jax.org
|
REFERENCES |
|---|
|
TOPABSTRACTPRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...PRIMARY MUTATIONS KNOWN TO...EVIDENCE FOR MODIFIERS OF...EVIDENCE FOR MODIFIERS OF...STRATEGIES FOR CLONING MODIFIER...SUMMARY/PERSPECTIVESREFERENCES |
|---|
1 Vineis, P. (2001) Diet, genetic susceptibility and carcinogenesis. Public Health Nutr., 4, 485–491.[Medline]
2 Mucci, L.A., Wedren, S., Tamimi, R.M., Trichopoulos, D. and Adami, H.O. (2001) The role of gene–environment interaction in the etiology of human cancer: examples from cancers of the large bowel, lung and breast. J. Intern Med., 249, 477–493.[Web of Science][Medline]
3 Whalley, L.J. (2001) Early-onset Alzheimer's disease in Scotland: environmental and familial factors. Br. J. Psychiatry, 40(Suppl.), s53–s59.
4 Hokanson, J.E. (1999) Functional variants in the lipoprotein lipase gene and risk cardiovascular disease. Curr. Opin. Lipidol., 10, 393–399.[Web of Science][Medline]
5 Zielenski, J. (2000) Genotype and phenotype in cystic fibrosis. Respiration, 67, 117–133.[Web of Science][Medline]
6 Friedman, T., Battey, J., Kachar, B., Riauddin, S., Noben-Trauth, K., Griffith, A. and Wilcox, E. (2000) Modifiers of hereditary hearing loss. Curr. Opin. Neurobiol., 10, 487–493.[Web of Science][Medline]
7
Weleber, R.G., Carr, R.E., Murphey, W.H., Sheffield, V.C. and Stone, E.M. (1993) Phenotypic variation including retinitis pigmentosa, pattern dystrophy, and fundus flavimaculatus in a single family with a deletion of codon 153 or 154 of the peripherin/RDS gene. Arch. Ophthal., 111, 1531–1542.
8
Kajiwara, K., Berson, E.L. and Dryja, T.P. (1994) Digenic retinitis pigmentosa due to mutations at the unlinked peripherin/RDS and ROM1 loci. Science, 264, 1604–1608.
9
Jacobson, S.G., Cideciyan, A.V., Iannaccone, A., Weleber, R.G., Fishman, G.A., Maguire, A.M., Affatigato, L.M., Bennett, J., Pierce, E.A., Danciger, M. et al. (2000) Disease expression of RP1 mutations causing autosomal dominant retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci., 41, 1898–1908.
10 Craig, J.E., Baird, P.N., Healey, D.L., McNaught, A.I., McCartney, P.J., Rait, J.L., Dickinson, J.L., Roe, L., Fingert, J.H., Stone, E.M. and Mackey, D.A. (2001) Evidence for genetic heterogeneity within eight glaucoma families, with the GLC1A Gln368STOP mutation being an important phenotypic modifier. Ophthalmol., 108, 1607–1620.
11
Riise, R., Andreasson, S., Borgastrom, M.K., Wright, A.F., Tommerup, N., Rosenberg, T. and Tornqvist, K. (1997) Intrafamilial variation of the phenotype in Bardet–Biedl syndrome. Br. J. Ophthalmol., 81, 378–385.
12 Carmi, R., Elbedour, K., Stone, E.M. and Sheffield, V.C. (1995) Phenotypic differences among patients with Bardet–Biedl syndrome linked to three different chromosome loci. Am. J. Med. Genet., 59, 199–203.[Web of Science][Medline]
13 Slavotinek, A.M., Stone, E.M., Mykytyn, K., Heckenlively, J.R., Green, J.S., Heon, E., Musarella, M.A., Parfrey, P.S., Sheffield, V.C. and Biesecker, L.G. (2000) Mutations in MKKS cause Bardet–Biedl syndrome. Nat. Genet., 26, 15–16.[Web of Science][Medline]
14 Katsanis, N., Beales, P.L., Woods, M.O., Lewis, R.A., Green, J.S., Parfrey, P.S., Ansley, S.J., Davidson, W.S. and Lupski, J.R. (2000) Mutations in MKKS cause obesity, retinal dystrophy and renal malformations associated with Bardet–Biedl syndrome. Nat. Genet., 26, 67–70.[Web of Science][Medline]
15
Nishimura, D.Y., Searby, C.C., Carmi, R., Elbedour, K., Van Maldergem, L., Fulton, A.B., Lam, B.L., Powell, B.R., Swiderski, R.E., Bugge, K.E. et al. (2001) Positional cloning of a novel gene on chromosome 16q causing Bardet–Biedl syndrome (BBS2). Hum. Mol. Genet., 10, 865–874.
16 Mykytyn, K., Braun, T., Carmi, R., Haider, N.B., Searby, C.C., Shastri, M., Beck, G., Wright, A.F., Iannaccone, A., Elbedour, K. et al. (2001) Identification of the gene that, when mutated, causes the human obesity syndrome BBS4. Nat. Genet., 28, 188–191.[Web of Science][Medline]
17
Katsanis, N., Ansley, S.J., Badano, J.L., Eichers, E.R., Lewis, R.A., Hoskins, B.E., Scambler, P.J., Davidson, W.S., Beales, P.L. and Lupski, J.R. (2001) Triallelic inheritance in Bardet–Biedl syndrome, a Mendelian recessive disorder. Science, 293, 2256–2259.
18
Burghes, A.H., Vaessin, H.E. and de La Chapelle, A. (2001) Genetics. The land between Mendelian and multifactorial inheritance. Science, 293, 2213–2214.
19 Hummel, K.P., Coleman, D.L. and Lane, P.W. (1972) The influence of genetic background on expression of mutations at the diabetes locus in the mouse. I. C57BL-KsJ and C57BL-6J strains. Biochem. Genet., 7, 1–13.[Web of Science][Medline]
20
Ikeda, S., Hawes, N.L., Chang, B., Avery, C.S., Smith, R.S. and Nishina, P.M. (1999) Ocular abnormalities in C57BL/6 but not 129/Sv p53 deficient mice. Invest. Ophthalmol. Vis. Sci., 40, 1874–1878.
21
Cepko, C.L., Austin, C.P., Yang, X., Alexiades, M. and Ezzeddine, D. (1996) Cell fate determination in the vertebrate retina. Proc. Natl Acad. Sci. USA, 93, 589–595.
22 Kume, T., Deng, K.-Y., Winfrey, W., Gould, D.B., Walter, M.A. and Hogan, B.L.M. (1998) The forkhead/winged helix gene Mf1 is disrupted in the pleiotropic mouse mutation congenital hydrocephalus. Cell, 93, 985–996.[Web of Science][Medline]
23
Hong, H.K., Lass, J.H. and Chakravarti, A. (1999) Pleiotropic skeletal and ocular phenotypes of the mouse mutation congenital hydrocephalus (ch/Mf1) arise from a winged helix/forkhead transcription factor gene. Hum. Mol. Genet., 8, 625–637.
24 Chang, B., Smith, R.S., Peters, M., Savinova, O.V., Hawes, N.L., Zabaleta, A., Nusinowitz, S., Martin, J.E., Davisson, M.L., Cepko, C.L. et al. (2001) Haploinsufficient Bmp4 ocular phenotypes include anterior segment dysgenesis with elevated intraocular pressure. B.M.C. Genet., 2, 18.[Medline]
25 Theiler, K., Varnum, D.S., Nadeau, J.H., Stevens, L.C. and Cagianut, B. (1976) A new allele of ocular retardation: early development and morphogenetic cell death. Anat. Embryol., 150, 85–97.[Medline]
26 Bone-Larson, C., Basu, S., Radel, J.D., Liang, M., Perozek, T., Kapousta-Bruneau, N., Green, D.G., Burmeister, M. and Hankin, M.H. (2000) Partial rescue of the ocular retardation phenotype by genetic modifiers. J. Neurobiol., 42, 232–247.[Web of Science][Medline]
27 Maeda, Y.Y., Funata, N., Takahama, S., Sugata, Y. and Yonekawa, H. (2001) Two interactive genes responsible for a new inherited cataract (RCT) in the mouse. Mamm. Genome, 12, 278–283.[Web of Science][Medline]
28 Humphries, M.M., Kiang, S., McNally, N., Donovan, M.A., Sieving, P.A., Bush, R.A., Machida, S., Cotter, T., Hobson, A., Farrar, J. et al. (2001) Comparative structural and functional analysis of photoreceptor neurons of Rho-/- mice reveal increased survival on C57BL/6J in comparison to 129Sv genetic background. Vis. Neurosci., 18, 437–443.[Web of Science][Medline]
29 Ikeda, A., Naggert, J.K. and Nishina, P.M. (2002) Genetic modification of retinal degeneration in tubby mice. Exp. Eye Res. (in press).
30 Resendes, B.L., Williamson, R.E. and Morton, C.C. (2001) At the speed of sound: gene discovery in the auditory system. Am. J. Hum. Genet., 69, 923–935.[Web of Science][Medline]
31 Steel, K.P. and Kros, C.J. (2001) A genetic approach to understanding auditory function. Nat. Genet., 27, 143–149.[Web of Science][Medline]
32 Balciuniene, J., Dahl, N., Jalonen, P., Verhoeven, K., Van Camp, G., Borg, E., Pettersson, U. and Jazin, E.E. (1999) Alpha-tectorin involvement in hearing disabilities: one gene–two phenotypes. Hum. Genet., 105, 211–216.[Web of Science][Medline]
33 Riazuddin, S., Castelein, C.M., Ahed, Z.M., Lalwani, A.K., Mastroianni, M.A., Naz, S., Smith, T.N., Liburd, N.A., Friedman, T.B., Griffith, A.J. et al. (2000) Dominant modifier DFNM1 suppresses recessive deafness DFNB26. Nat. Genet., 26, 431–433.[Web of Science][Medline]
34 Salam, A.A., Hafner, F.M., Linder, T.E., Spillmann, T., Schinzel, A.A. and Leal, S.M. (2000) A novel locus (DFNA23) for prelingual autosomal dominant nonsyndromic hearing loss maps to 14q21–q22 in a Swiss German kindred. Am. J. Hum. Genet., 66, 1984–1988.[Web of Science][Medline]
35
Cohn, E.S., Kelley, P.M., Fowler, T.W., Gorga, M.P., Lefkowitz, D.M., Kuehn, H.J., Schaefer, G.B., Gobar, L.S., Hahn, F.J., Harris, D.J. and Kimberling, W.J. (1999) Clinical studies of families with hearing loss attributable to mutations in the connexin 26 gene (GJB2/DFNB1). Pediatrics, 103, 546–550.
36 Bykhovskaya, Y., Estivill, X., Taylor, K., Hang, T., Hamon, M., Casano, R.A., Yang, H., Rotter, J.I., Shohat, M. and Fischel-Ghodsian, N. (2000) Candidate locus for a nuclear modifier gene for maternally inherited deafness. Am. J. Hum. Genet., 66, 1905–1910.[Web of Science][Medline]
37 Steel, K.P. (1995) Inherited hearing defects in mice. Annu. Rev. Genet., 29, 675–701.[Web of Science][Medline]
38 Noben-Trauth, K., Zheng, Q.Y., Johnson, K.R. and Nishina, P.M. (1997) mdfw: a deafness susceptibility locus that interacts with deaf waddler (dfw). Genomics, 44, 266–272.[Web of Science][Medline]
39 Street, V.A., McKee-Johnson, J.W., Fonseca, R.C., Tempel, B.L. and Noben-Trauth, K. (1998) Mutations in a plasma membrane Ca2+-ATPase gene cause deafness in deafwaddler mice. Nat. Genet., 19, 390–394.[Web of Science][Medline]
40 Johnson, K.R., Erway, L.C., Cook, S.A., Willott, J.F. and Zheng, Q.Y. (1997) A major gene affecting age-related hearing loss in C57BL/6J mice. Hearing Res., 114, 83–92.[Web of Science][Medline]
41 Zheng, Q.Y. and Johnson, K.R. (2001) Hearing loss associated with the modifier of deaf waddler (mdfw) locus corresponds with age-related hearing loss in 12 inbred strains of mice. Hearing Res., 154, 45–53.[Web of Science][Medline]
42 Bryda, E.C., Kim, H.J., Leagare, M.E., Frankel, W.N. and Noben-Trauth, K. (2001) High resolution genetic and physical mapping of modifier-of-deafwaddler (mdfw) and Waltzer (Cdh23v). Genomics, 73, 338–342.[Web of Science][Medline]
43
Ikeda, A., Zheng, Q.Y., Rosenstiel, P., Maddatu, T., Zuberi, A.R., Roopenian, D.C., North, M.A., Naggert, J.K., Johnson, K.R. and Nishina, P.M. (1999) Genetic modification of hearing in tubby mice: evidence for the existence of a major gene (moth1) which protects tubby mice from hearing loss. Hum. Mol. Genet., 8, 1761–1767.
44 Ikeda, A., Zheng, Q.Y., Zuberi, A.R., Johnson, K.R., Naggert, J.K. and Nishina, P.M. (2002) Microtubule-associated protein 1A is a modifier of tubby hearing (moth1). Nat. Genet., 30, 401–405.[Web of Science][Medline]
45
Brenman, J.E., Topinka, J.R., Cooper, E.C., McGee, A.W., Rosen, J., Milroy, T., Ralston, H.J. and Bredt, D.S. (1998) Localization of postsynaptic density-93 to dendritic microtubules and interaction with microtubule-associated protein 1A. J. Neurosci., 18, 8805–8813.
46 Thomas, U., Ebitsch, S., Gorczyca, M., Koh, Y.H., Hough, C.D., Woods, D., Gundelfinger, E.D. and Budnik, V. (2000) Synaptic targeting and localization of Disc-large is a stepwise process controlled by different domains of the protein. Current Biol., 10, 1108–1117.[Web of Science][Medline]
47 Johnson, K.R., Zheng, Q.Y., Bykhovskaya, Y., Spirina, O. and Fischel-Ghodsian, N. (2001) A nuclear-mitochondrial DNA interaction affecting hearing impairment in mice. Nat. Genet., 27, 191–194.[Web of Science][Medline]
48 Naggert, J.K. and Nishina, P.M. (2002) Genetic approaches to identifying QTL and modifiers of hereditary ocular phenotypes. In: Smith RS, John SWM, Nishina PM and Sundberg JP (eds), Systematic Evaluation of the Mouse Eye: Anatomy, Pathology, and Biomethods. CRC Press, Boca Raton, FL, pp. 81–92.
49 Avraham, K.B. (2001) Positional-candidate cloning of genes from mouse mutants. Meth. Mol. Biol., 158, 369–379.[Medline]
50 Boissy, R.E., Zhao, H., Oetting, W.S., Austin, L.M., Wildenberg, S.C., Boissy, Y.L., Zhao, Y., Sturm, R.A., Hearing, V.J., King, R.A. and Nordlund, J.J. (1996) Mutation in and lack of expression of tyrosinase-related protein-1 (TRP-1) in melanocytes from an individual with brown oculocutaneous albinism: a new subtype of albinism classified as ‘OCA3’. Am. J. Hum. Genet., 58, 1145–1156.[Web of Science][Medline]
51 Manga, P., Kromberg, J.G.R., Box, N.F., Sturm, R.A., Jenkins, T. and Ramsay, M. (1997) Rufous oculocutaneous albinism in southern African blacks is caused by mutations in the TYRP1 gene. Am. J. Hum. Genet., 61, 1095–1101.[Web of Science][Medline]
52 Anderson, M.G., Smith, R.S., Hawes, N.L., Zabaleta, A., Chang, B., Wiggs, J.L. and John, S.W. (2002) Mutations in genes encoding melanosomal proteins cause pigmentary glaucoma in DBA/2J mice. Nat. Genet., 30, 81–85.[Web of Science][Medline]
53
Litt, M., Kramer, P., LaMorticella, D.M., Murphey, W., Lovrien, E.W. and Weleber, R.G. (1998) Autosomal dominant congenital cataract associated with a missense mutation in the human alpha crystallin gene CRYAA. Hum. Mol. Genet., 7, 471–474.
54
Brady, J.P., Garland, D., Duglas-Tabor, Y., Robison, W.G., Jr, Groome, A. and Wawrousek, E.F. (1997) Targeted disruption of the mouse alpha A-crystallin gene induces cataract and cytoplasmic inclusion bodies containing the small heat shock protein alpha B-crystallin. Proc. Natl Acad. Sci. USA, 94, 884–889.
55 Chang, B., Hawes, N.L., Roderick, T.H., Smith, R.S., Heckenlively, J.R., Horwitz, J. and Davisson, M.T. (1999) Identification of a missense mutation in the alphaA-crystallin gene of the lop18 mouse. Mol. Vis., 10, 5:21.
56 den Hollander, A.I., ten Brink, J.B., de Kok, Y.J., van Soest, S., van den Born, L.I., van Driel, M.A., van de Pol, D.J., Payne, A.M., Bhattacharya, S.S., Kellner, U. et al. (1999) Mutations in a human homologue of Drosophila crumbs cause retinitis pigmentosa (RP12). Nat. Genet., 23, 217–221.[Web of Science][Medline]
57 den Hollander, A.I., Heckenlively, J.R., van den Born, L.I., de Kok, Y.J., van der Velde-Visser, S.D., Kellner, U., Jurklies, B., van Schooneveld, M.J., Blankenagel, A., Rohrschneider, K. et al. (2001) Leber congenital amaurosis and retinitis pigmentosa with Coats-like exudative vasculopathy are associated with mutations in the crumbs homologue 1 (CRB1) gene. Am. J. Hum. Genet., 69, 198–203.[Web of Science][Medline]
58 Lotery, A.J., Malik, A., Shami, S.A., Sindhi, M., Chohan, B., Maqbool, C., Moore, P.A., Denton, M.J. and Stone, E.M. (2001) CRB1 mutations may result in retinitis pigmentosa without para-arteriolar RPE preservation. Ophthalmic Genet., 22, 163–169.[Medline]
59 van Soest, S., Ingeborgh van den Born, L., Gal, A., Farrar, G.J., Bleeker-Wagemakers, L.M., Westerveld, A., Humphries, P., Sandkuijl, L.A. and Bergen, A.A. (1994) Assignment of a gene for autosomal recessive retinitis pigmentosa (RP12) to chromosome 1q31–q32.1 in an inbred and genetically heterogeneous disease population. Genomics, 22, 499–504.[Web of Science][Medline]
60
Stephan, D.A., Gillanders, E., Vanderveen, D., Freas-Lutz, D., Wistow, G., Baxevanis, A.D., Robbins, C.M., VanAuken, A., Quesenberry, M.I., Bailey-Wilson, J. et al. (1999) Progressive juvenile-onset punctate cataracts caused by mutation of the gammaD-crystallin gene. Proc. Natl Acad. Sci. USA, 96, 1008–1012.
61 Smith, R.S., Hawes, N.L., Chang, B., Roderick, T.H., Akeson, E.C., Heckenlively, J.R., Gong, X., Wang, X. and Davisson, M.T. (2000) Lop12, a mutation in mouse Crygd causing lens opacity similar to human Coppock cataract. Genomics., 63, 314–320.[Web of Science][Medline]
62 Bessant, D.A., Payne, A.M., Mitton, K.P., Wang, Q.L., Swain, P.K., Plant, C., Bird, A.C., Zack, D.J., Swaroop, A. and Bhattacharya, S.S. (1999) A mutation in NRL is associated with autosomal dominant retinitis pigmentosa. Nat. Genet., 21, 355–356.[Web of Science][Medline]
63 Mears, A.J., Kondo, M., Swain, P.K., Takada, Y., Bush, R.A., Saunders, T.L., Sieving, P.A. and Swaroop, A. (2001) Nrl is required for rod photoreceptor development. Nat. Genet., 29, 447–452.[Web of Science][Medline]
64 Banerjee, P., Kleyn, P.W., Knowles, J.A., Lewis, C.A., Ross, B.M., Parano, E., Kovats, S.G., Lee, J.J., Penchaszadeh, G.K., Ott, J. et al. (1998) TULP1 mutation in two extended Dominican kindreds with autosomal recessive retinitis pigmentosa. Nat. Genet., 18, 177–179.[Web of Science][Medline]
65
Hagstrom, S.A., Duyao, M., North, M.A. and Li, T. (1999) Retinal degeneration in tulp1-/- mice: vesicular accumulation in the interphotoreceptor matrix. Invest. Ophthalmol. Vis. Sci., 40, 2795–2802.
66 Ikeda, S., Shiva, N., Ikeda, A., Smith, R.S., Nusinowitz, S., Yan, G., Lin, T.R., Chu, S., Heckenlively, J.R., North, M.A. et al. (2000) Retinal degeneration but not obesity is observed in null mutants of the tubby-like protein 1 gene. Hum. Mol. Genet., 22, 155–163.
67 Sullivan, L.S., Heckenlively, J.R., Bowne, S.J., Zuo, J., Hide, W.A., Gal, A., Denton, M., Inglehearn, C.F., Blanton, S.H. and Daiger, S.P. (1999) Mutations in a novel retina-specific gene cause autosomal dominant retinitis pigmentosa. Nat. Genet., 22, 255–259.[Web of Science][Medline]
68 Jacobson, S.G., Cideciyan, A.V., Iannaccone, A., Weleber, R.G., Fishman, G.A., Maguire, A.M., Affatigato, L.M., Bennett, J., Pierce, E.A., Danciger, M., et al. (2000) Disease expression of RP1 mutations causing autosomal dominant retinitis pigmentosa. Invest. Ophthalmol. Vis. Sci., 41, 1898–1908.
69 Mackay, D., Ionides, A., Kibar, Z., Rouleau, G., Berry, V., Moore, A., Shiels, A. and Bhattacharya, S. (1999) Connexin46 mutations in autosomal dominant congenital cataract. Am. J. Hum. Genet., 64, 1357–1364.[Web of Science][Medline]
70 Gong, X., Agopian, K., Kumar, N.M. and Gilula, N.B. (1999) Genetic factors influence cataract formation in alpha 3 connexin knockout mice. Dev. Genet., 24, 27–32.[Web of Science][Medline]
71
Bateman, J.B., Geyer, D.D., Flodman, P., Johannes, M., Sikela, J., Walter, N., Moreira, A.T., Clancy, K. and Spence, M.A. (2000) A new betaA1-crystallin splice junction mutation in autosomal dominant cataract. Invest. Ophthalmol. Vis. Sci., 41, 3278–3285.
72 Graw, J., Jung, M., Loster, J., Klopp, N., Soewarto, D., Fella, C., Fuchs, H., Reis, A., Wolf, E., Balling, R. and Hrabe de Angelis, M. (1999) Mutation in the betaA3/A1-crystallin encoding gene Cryba1 causes a dominant cataract in the mouse. Genomics., 62, 67–73.[Web of Science][Medline]
73 Bech-Hansen, N.T., Naylor, M.J., Maybaum, T.A., Sparkes, R.L., Koop, B., Birch, D.G., Bergen, A.A., Prinsen, C.F., Polomeno, R.C., Gal, A. et al. (2000) Mutations in NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness. Nat. Genet., 26, 319–323.[Web of Science][Medline]
74
Candille, S.I., Pardue, M.T., McCall, M.A., Peachey, N.S. and Gregg, R.G. (1999) Localization of the mouse nob (no b-wave) gene to the centromeric region of the X chromosome. Invest. Ophthalmol. Vis. Sci., 40, 2748–2751.
75
Maw, M.A., Corbeil, D., Koch, J., Hellwig, A., Wilson-Wheeler, J.C., Bridges, R.J., Kumaramanickavel, G., John, S., Nancarrow, D., Roper, K. et al. (2000) A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum. Mol. Genet., 9, 27–34.
76
Kohl, S., Baumann, B., Broghammer, M., Jagle, H., Sieving, P., Kellner, U., Spegal, R., Anastasi, M., Zrenner, E., Sharpe, L.T. and Wissinger, B. (2000) Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21. Hum. Mol. Genet., 9, 2107–2116.
77 Verpy, E., Leibovici, M., Zwaenepoel, I., Liu, X.Z., Gal, A., Salem, N., Mansour, A., Blanchard, S., Kobayashi, I., Keats, B.J. et al. (2000) A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C. Nat. Genet., 26, 51–55.[Web of Science][Medline]
78 Bitner-Glindzicz, M., Lindley, K.J., Rutland, P., Blaydon, D., Smith, V.V., Milla, P.J., Hussain, K., Furth-Lavi, J., Cosgrove, K.E., Shepherd, R.M. et al. (2000) A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Nat. Genet., 26, 56–60.[Web of Science][Medline]
79 Haider, N.B., Jacobson, S.G., Cideciyan, A.V., Swiderski, R., Streb, L.M., Searby, C., Beck, G., Hockey, R., Hanna, D.B., Gorman, S. et al. (2000) Mutation of a nuclear receptor gene, NR2E3, causes enhanced S cone syndrome, a disorder of retinal cell fate. Nat. Genet., 24, 127–131.[Web of Science][Medline]
80 Jacobson, S.G., Roman, A.J., Roman, M.I., Gass, J.D. and Parker, J.A. (1991) Relatively enhanced S cone function in the Goldmann–Favre syndrome. Am. J. Ophthalmol., 111, 446–453.[Web of Science][Medline]
81
Fishman, G.A., Jampol, L.M. and Goldberg, M.F. (1976) Diagnostic features of the Favre–Goldmann syndrome. Br. J. Ophthalmol., 60, 345–353.
82 Fishman, G.A. and Peachey, N.S. (1989) Rod-cone dystrophy associated with a rod system electroretinogram obtained under photopic conditions. Ophthalmology, 96, 913–918.[Web of Science][Medline]
83 Favre, M. (1958) A propos de deux cas de dégénérescence hyaloideorétinienne. Ophthalmologica, 135, 604–609.[Medline]
84
Akhmedov, N.B., Piriev, N.I., Chang, B., Rapoport, A.L., Hawes, N.L., Nishina, P.M., Nusinowitz, S., Heckenlively, J.R., Roderick, T.H., Kozak, C.A. et al. (2000) A deletion in a photoreceptor-specific nuclear receptor mRNA causes retinal degeneration in the rd7 mouse. Proc. Natl Acad. Sci. USA, 97, 5551–5556.
85
Sertie, A.L., Sossi, V., Camargo, A.A., Zatz, M., Brahe, C. and Passos-Bueno, M.R. (2000) Collagen XVIII, containing an endogenous inhibitor of angiogenesis and tumor growth, plays a critical role in the maintenance of retinal structure and in neural tube closure (Knobloch syndrome). Hum. Mol. Genet., 9, 2051–2058.
86
Blixt, A., Mahlapuu, M., Aitola, M., Pelto-Huikko, M., Enerback, S. and Carlsson, P. (2000) A forkhead gene, FoxE3, is essential for lens epithelial proliferation and closure of the lens vesicle. Genes. Dev., 14, 245–254.
87 Cox, G.A., Mahaffey, C.L., Nystuen, A., Letts, V.A. and Frankel, W.N. (2000) The mouse fidgetin gene defines a new role for AAA family proteins in mammalian development. Nat. Genet., 26, 198–202.[Web of Science][Medline]
88 Joensuu, T., Hamalainen, R., Yuan, B., Johnson, C., Tegelberg, S., Gasparini, P., Zelante, L., Pirvola, U., Pakarinen, L., Lehesjoki, A.E. et al. (2001) Mutations in a novel gene with transmembrane domains underlie Usher syndrome type 3. Am. J. Hum. Genet., 69, 673–684.[Web of Science][Medline]
89
Edwards, A.O., Donoso, L.A. and Ritter, R., 3rd (2001) A novel gene for autosomal dominant Stargardt-like macular dystrophy with homology to the SUR4 protein family. Invest. Ophthalmol. Vis. Sci., 42, 2652–2663.
90 Zhang, K., Kniazeva, M., Han, M., Li, W., Yu, Z., Yang, Z., Li, Y., Metzker, M.L., Allikmets, R., Zack, D.J. et al. (2001) A 5-bp deletion in ELOVL4 is associated with two related forms of autosomal dominant macular dystrophy. Nat. Genet., 27, 89–93.[Web of Science][Medline]
91
Alagramam, K.N., Yuan, H., Kuehn, M.H., Murcia, C.L., Wayne, S., Srisailpathy, C.R., Lowry, R.B., Knaus, R., Van Laer, L., Bernier, F.P. et al. (2001) Mutations in the novel protocadherin PCDH15 cause Usher syndrome type 1F. Hum. Mol. Genet., 10, 1709–1718.
92 Ahmed, Z.M., Riazuddin, S., Bernstein, S.L., Ahmed, Z., Khan, S., Griffith, A.J., Morell, R.J., Friedman, T.B., Riazuddin, S. and Wilcox, E.R. (2001) Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F. Am. J. Hum. Genet., 69, 25–34.[Web of Science][Medline]
93 Alagramam, K.N., Murcia, C.L., Kwon, H.Y., Pawlowski, K.S., Wright, C.G. and Woychik, R.P. (2001) The mouse Ames waltzer hearing-loss mutant is caused by mutation of Pcdh15, a novel protocadherin gene. Nat. Genet., 27, 99–102.[Web of Science][Medline]
94 Bork, J.M., Peters, L.M., Riazuddin, S., Bernstein, S.L., Ahmed, Z.M., Ness, S.L., Polomeno, R., Ramesh, A., Schloss, M., Srisailpathy, C.R. et al. (2001) Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am. J. Hum. Genet., 68, 26–37.[Web of Science][Medline]
95 Bolz, H., von Brederlow, B., Ramirez, A., Bryda, E.C., Kutsche, K., Nothwang, H.G., Seeliger, M., Cabrera, M.C.S., Vila, M.C., Molina, O.P. et al. (2001) Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nat. Genet., 27, 108–112.[Web of Science][Medline]
96 Di Palma, F., Holme, R.H., Bryda, E.C., Belyantseva, I.A., Pellegrino, R., Kachar, B., Steel, K.P. and Noben-Trauth, K. (2001) Mutations in Cdh23, encoding a new type of cadherin, cause stereocilia disorganization in waltzer, the mouse model for Usher syndrome type 1D. Nat. Genet., 27, 103–107.[Web of Science][Medline]
97
McKie, A.B., McHale, J.C., Keen, T.J., Tarttelin, E.E., Goliath, R., van Lith-Verhoeven, J.J., Greenberg, J., Ramesar, R.S., Hoyng, C.B., Cremers, F.P. et al. (2001) Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominant retinitis pigmentosa (RP13). Hum. Mol. Genet., 10, 1555–1562.
98 Vithana, E.N., Abu-Safieh, L., Allen, M.J., Carey, A., Papaioannou, M., Chakarova, C., Al-Maghtheh, M., Ebenezer, N.D., Willis, C., Moore, A.T. et al. (2001) A human homolog of yeast pre-mRNA splicing gene, PRP31, underlies autosomal dominant retinitis pigmentosa on chromosome 19q13.4 (RP11). Mol. Cell., 8, 375–381.[Web of Science][Medline]
99 McGee, T.L., Devoto, M., Ott, J., Berson, E.L. and Dryja, T.P. (1997) Evidence that the penetrance of mutations at the RP11 locus causing dominant retinitis pigmentosa is influenced by a gene linked to the homologous RP11 allele. Am. J. Hum. Genet., 61, 1059–1066.[Web of Science][Medline]
100 Gao, H., Boustany, R.M., Espinola, J.A., Cotman, S.L., Srinidhi, L., Antonellis, K.A., Gillis, T., Qin, X., Liu, S., Donahue, L.R., Bronson, R.T. et al. (2002) Mutations in a novel CLN6-encoded transmembrane protein cause variant neuronal ceroid lipofuscinosis in man and mouse. Am. J. Hum. Genet., 70, 324–335.[Web of Science][Medline]
101 Wheeler, R.B., Sharp, J.D., Schultz, R.A., Joslin, J.M., Williams, R.E. and Mole, S.E. (2002) The gene mutated in variant late-infantile neuronal ceroid lipofuscinosis (CLN6) and in nclf mutant mice encodes a novel predicted transmembrane protein. Am. J. Hum. Genet., 70, 537–542.[Web of Science][Medline]
102
Zhou, G. and Williams, R.W. (1999) Eye1 and Eye2: gene loci that modulate eye size, lens weight, and retinal area in the mouse. Invest. Ophthalmol. Vis. Sci., 40, 817–825.
103 Chang, B., Smith, R.S., Hawes, N.L., Anderson, M.G., Zabaleta, A., Savinova, O., Roderick, T.H., Heckenlively, J.R., Davisson, M.T. and John, S.W. (1999) Interacting loci cause severe iris atrophy and glaucoma in DBA/2J. Nat. Genet., 21, 405–409.[Web of Science][Medline]
104 Zhou, G. and Williams, R.W. (1999) Mouse models for the analysis of myopia: an analysis of variation in eye size of adult mice. Optomol. Vis. Sci., 76, 408–418.
105
Rohan, R.M., Fernandez, A., Udagawa, T., Yuan, J. and D'Amato, R.J. (2000) Genetic heterogeneity of angiogenesis in mice. FASEB J., 14, 871–876.
106 Danciger, M., Matthes, M.T., Yasamura, D., Akhmedov, N.B., Rickabaugh, T., Gentleman, S., Redmond, T.M., La Vail, M.M. and Farber, D.B. (2000) A QTL on distal chromosome 3 that influences the severity of light-induced damage to mouse photoreceptors. Mamm. Genome, 11, 422–427.[Web of Science][Medline]
107 McGuirt, W.T., Prasad, S.D., Griffith, A.J., Kunst, H.P., Green, G.E., Shpargel, K.B., Runge, C., Huybrechts, C., Mueller, R.F., Lynch, E. et al. (1999) Mutations in COL11A2 cause non-syndromic hearing loss (DFNA13). Nat. Genet., 23, 413–419.[Web of Science][Medline]
108 Karet, F.E., Finberg, K.E., Nelson, R.D., Nayir, A., Mocan, H., Sanjad, S.A., Rodriguez-Soriano, J., Santos, F., Cremers, C.W., Di Pietro, A. et al. (1999) Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Nat. Genet., 21, 84–90.[Web of Science][Medline]
109 Kubisch, C., Schroeder, B.C., Friedrich, T., Lutjohann, B., El-Amraoui, A., Marlin, S., Petit, C. and Jentsch, T.J. (1999) KCNQ4, a novel potassium channel expressed in sensory outer hair cells, is mutated in dominant deafness. Cell, 96, 437–446.[Web of Science][Medline]
110 Marres, H., van Ewijk, M., Huygen, P., Kunst, H., van Camp, G., Coucke, P., Willems, P. and Cremers, C. (1997) Inherited nonsyndromic hearing loss. An audiovestibular study in a large family with autosomal dominant progressive hearing loss related to DFNA2. Arch. Otolaryngol. Head Neck Surg., 123, 573–577.
111 Yasunaga, S., Grati, M., Cohen-Salmon, M., El-Amraoui, A., Mustapha, M., Salem, N., El-Zir, E., Loiselet, J. and Petit, C. (1999) A mutation in OTOF, encoding otoferlin, a FER-1-like protein, causes DFNB9, a nonsyndromic form of deafness. Nat Genet., 21, 363–369.[Web of Science][Medline]
112 Kovach, M.J., Lin, J.P., Boyadjiev, S., Campbell, K., Mazzeo, L., Herman, K., Rimer, L.A., Frank, W., Llewellyn, B., Wang Jabs, E. et al. (1999) A unique point mutation in the PMP22 gene is associated with Charcot-Marie-Tooth disease and deafness. Am. J. Hum. Genet., 64, 1580–1593.[Web of Science][Medline]
113 Suter, U., Welcher, A.A., Ozcelik, T., Snipes, G.J., Kosaras, B., Francke, U., Billings-Gagliardi, S., Sidman, R.L. and Shooter, E.M. (1992) Trembler mouse carries a point mutation in a myelin gene. Nature, 356, 241–244.[Medline]
114 Grifa, A., Wagner, C.A., D'Ambrosio, L., Melchionda, S., Bernardi, F., Lopez-Bigas, N., Rabionet, R., Arbones, M., Monica, M.D., Estivill, X. et al. (1999) Mutations in GJB6 cause nonsyndromic autosomal dominant deafness at DFNA3 locus. Nat. Genet., 23, 16–18.[Web of Science][Medline]
115 Kelley, M.J., Jawien, W., Ortel, T.L. and Korczak, J.F. (2000) Mutation of MYH9, encoding non-muscle myosin heavy chain A, in May–Hegglin anomaly. Nat. Genet., 26, 106–108.[Web of Science][Medline]
116 Seri, M., Cusano, R., Gangarossa, S., Caridi, G., Bordo, D., Lo Nigro, C., Ghiggeri, G.M., Ravazzolo, R., Savino, M., Del Vecchio, M. et al. (2000) Mutations in MYH9 result in the May–Hegglin anomaly, and Fechtner and Sebastian syndromes. The May–Heggllin/Fechtner Syndrome Consortium. Nat. Genet., 26, 103–105.[Web of Science][Medline]
117 Wilcox, E.R., Burton, Q.L., Naz, S., Riazuddin, S., Smith, T.N., Ploplis, B., Belyantseva, I., Ben-Yosef, T., Liburd, N.A., Morell, R.J. et al. (2001) Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29. Cell, 104, 165–172.[Web of Science][Medline]
118 Scott, H.S., Kudoh, J., Wattenhofer, M., Shibuya, K., Berry, A., Chrast, R., Guipponi, M., Wang, J., Kawasaki, K., Asakawa, S. et al. (2001) Insertion of beta-satellite repeats identifies a transmembrane protease causing both congenital and childhood onset autosomal recessive deafness. Nat. Genet., 27, 59–63.[Web of Science][Medline]
119
Wayne, S., Robertson, N.G., DeClau, F., Chen, N., Verhoeven, K., Prasad, S., Tranebjarg, L., Morton, C.C., Ryan, A.F., Van Camp, G. and Smith, R.J. (2001) Mutations in the transcriptional activator EYA4 cause late-onset deafness at the DFNA10 locus. Hum. Mol. Genet., 10, 195–200.
120 Melchionda, S., Ahituv, N., Bisceglia, L., Sobe, T., Glaser, F., Rabionet, R., Arbones, M.L., Notarangelo, A., Di Iorio, E., Carella, M. et al. (2001) MYO6, the human homologue of the gene responsible for deafness in Snell's waltzer mice, is mutated in autosomal dominant nonsyndromic hearing loss. Am. J. Hum. Genet., 69, 635–640.[Web of Science][Medline]
121 Avraham, K.B., Hasson, T., Steel, K.P., Kingsley, D.M., Russell, L.B., Mooseker, M.S., Copeland, N.G. and Jenkins, N.A. (1995) The mouse Snell's waltzer deafness gene encodes an unconventional myosin required for structural integrity of inner ear hair cells. Nat. Genet., 11, 369–375.[Web of Science][Medline]
122
Bespalova, I.N., Van Camp, G., Bom, S.J., Brown, D.J., Cryns, K., DeWan, A.T., Erson, A.E., Flothmann, K., Kunst, H.P., Kurnool, P. et al. (2001) Mutations in the Wolfram syndrome 1 gene (WFS1) are a common cause of low frequency sensorineural hearing loss. Hum. Mol. Genet., 10, 2501–2508.
123
Young, T.L., Ives, E., Lynch, E., Person, R., Snook, S., MacLaren, L., Cator, T., Griffin, A., Fernandez, B., Lee, M.K. and King, M.C. (2001) Non-syndromic progressive hearing loss DFNA38 is caused by heterozygous missense mutation in the Wolfram syndrome gene WFS1. Hum. Mol. Genet., 10, 2509–2514.
124 Parkinson, N.J., Olsson, C.L., Hallows, J.L., McKee-Johnson, J., Keogh, B.P., Noben-Trauth, K. Kujawa, S.G. and Tempel, B.L. (2001) Mutant beta-spectrin 4 causes auditory and motor neuropathies in quivering mice. Nat. Genet., 29, 61–65.[Web of Science][Medline]
125
Ng, L., Rusch, A., Amma, L.L., Nordstrom, K., Erway, L.C., Vennstrom, B. and Forrest, D. (2001) Suppression of the deafness and thyroid dysfunction in Thrb-null mice by an independent mutation in the Thra thyroid hormone receptor alpha gene. Hum. Mol. Genet., 10, 2701–2708.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  T. Yamashita, J. Liu, J. Gao, S. LeNoue, C. Wang, J. Kaminoh, S. J. Bowne, L. S. Sullivan, S. P. Daiger, K. Zhang, et al. Essential and Synergistic Roles of RP1 and RP1L1 in Rod Photoreceptor Axoneme and Retinitis Pigmentosa J. Neurosci., August 5, 2009; 29(31): 9748 - 9760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Liu, A. Saveliev, and E. A. Pierce The Severity of Retinal Degeneration in Rp1h Gene-Targeted Mice Is Dependent on Genetic Background Invest. Ophthalmol. Vis. Sci., April 1, 2009; 50(4): 1566 - 1574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Noguchi, K. Kurima, T. Makishima, M. H. de Angelis, H. Fuchs, G. Frolenkov, K. Kitamura, and A. J. Griffith Multiple Quantitative Trait Loci Modify Cochlear Hair Cell Degeneration in the Beethoven (Tmc1Bth) Mouse Model of Progressive Hearing Loss DFNA36 Genetics, August 1, 2006; 173(4): 2111 - 2119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. L. Haywood-Watson II, Z. M. Ahmed, S. Kjellstrom, R. A. Bush, Y. Takada, L. L. Hampton, J. F. Battey, P. A. Sieving, and T. B. Friedman Ames waltzer deaf mice have reduced electroretinogram amplitudes and complex alternative splicing of pcdh15 transcripts. Invest. Ophthalmol. Vis. Sci., July 1, 2006; 47(7): 3074 - 3084. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Hauser, R. R. Allingham, K. Linkroum, J. Wang, K. LaRocque-Abramson, D. Figueiredo, C. Santiago-Turla, E. A. del Bono, J. L. Haines, M. A. Pericak-Vance, et al. Distribution of WDR36 DNA Sequence Variants in Patients with Primary Open-Angle Glaucoma. Invest. Ophthalmol. Vis. Sci., June 1, 2006; 47(6): 2542 - 2546. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Valleix, B. Nedelec, F. Rigaudiere, P. Dighiero, Y. Pouliquen, G. Renard, J.-F. Le Gargasson, and M. Delpech H244R VSX1 Is Associated with Selective Cone ON Bipolar Cell Dysfunction and Macular Degeneration in a PPCD Family Invest. Ophthalmol. Vis. Sci., January 1, 2006; 47(1): 48 - 54. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Willoughby, L. L. Y. Chan, S. Herd, G. Billingsley, N. Noordeh, A. V. Levin, Y. Buys, G. Trope, M. Sarfarazi, and E. Heon Defining the Pathogenicity of Optineurin in Juvenile Open-Angle Glaucoma Invest. Ophthalmol. Vis. Sci., September 1, 2004; 45(9): 3122 - 3130. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. L. Ball, D. Bardenstein, and K. N. Alagramam Assessment of Retinal Structure and Function in Ames Waltzer Mice Invest. Ophthalmol. Vis. Sci., September 1, 2003; 44(9): 3986 - 3992. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Slavotinek and L. G. Biesecker Genetic modifiers in human development and malformation syndromes, including chaperone proteins Hum. Mol. Genet., April 2, 2003; 12(90001): R45 - 50. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||