Human Molecular Genetics

Human Molecular Genetics Advance Access originally published online on February 19, 2004

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Human Molecular Genetics, 2004, Vol. 13, Review Issue 1 R65-R71
DOI: 10.1093/hmg/ddh092

The oligogenic properties of Bardet–Biedl syndrome

Nicholas Katsanis^*

Institute of Genetic Medicine and Wilmer Eye Institute, Johns Hopkins University, 600 North Wolfe Street, Baltimore, MD 21287, USA

Received January 29, 2004; Revised and Accepted February 9, 2004

	ABSTRACT

TOP ABSTRACT INTRODUCTION THE GENETIC CHALLENGE OF... GENE IDENTIFICATION IN BBS SECOND-SITE MODIFICATION IN BBS EVALUATION OF TRIALLELIC... AN EVOLVING VIEW OF... SOME NEW GENETIC LESSONS TOWARDS A CELLULAR AND... CONCLUSIONS REFERENCES

 
Bardet–Biedl syndrome (BBS: OMIM 209900) is a rare developmental disorder that exhibits significant clinical and genetic heterogeneity. Although modeled initially as a purely recessive trait, recent data have unmasked an oligogenic mode of disease transmission, in which mutations at different BBS loci can interact genetically in some families to cause and/or modify the phenotype. Here, I will review and discuss recent advances in elucidating both genetic and cellular aspects of this phenotype and their potential application in understanding the genetic basis of phenotypic variability and oligogenic inheritance.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION THE GENETIC CHALLENGE OF... GENE IDENTIFICATION IN BBS SECOND-SITE MODIFICATION IN BBS EVALUATION OF TRIALLELIC... AN EVOLVING VIEW OF... SOME NEW GENETIC LESSONS TOWARDS A CELLULAR AND... CONCLUSIONS REFERENCES

 
The last two decades have provided numerous examples whereby the genetic basis of human disease has been attributed convincingly to mutations at a specific locus. Such advances, however, have also raised significant new challenges. Most poignant is the realization that for the overwhelming majority of genes associated with Mendelian traits, knowledge of the genotype at a single locus can neither predict nor explain satisfactorily the phenotypic manifestations in any given patient or family (1–3). This has led to the exploration of second-site modification hypotheses and models, according to which alleles at additional loci influence the phenotypic outcome of mutations at a single locus, essentially de-Mendelizing monogenic traits (4).

Despite some success in quantifying second-site modification in humans (2,5) and model organisms (6,7), understanding the genetic, and ultimately biochemical, interactions of two genes and their products remains a difficult task. Some of the problems stem either from our limited ability to quantify the contribution of specific alleles to the phenotype (particularly perceived ‘weak’ alleles, such as some missense mutations) or from limited in vivo information about the biochemical and cellular properties of the gene product under investigation.

Bardet–Biedl syndrome (BBS) is a potentially useful phenotype to investigate some of these issues, since the disease can segregate in families both as a classical autosomal recessive and a digenic trait. Moreover, functional information is beginning to emerge about the cellular role of the BBS proteins, offering the possibility of modeling the cellular basis of the genetic interaction and applying the lessons learned to oligogenic and complex traits.

	THE GENETIC CHALLENGE OF BBS

TOP ABSTRACT INTRODUCTION THE GENETIC CHALLENGE OF... GENE IDENTIFICATION IN BBS SECOND-SITE MODIFICATION IN BBS EVALUATION OF TRIALLELIC... AN EVOLVING VIEW OF... SOME NEW GENETIC LESSONS TOWARDS A CELLULAR AND... CONCLUSIONS REFERENCES

 
BBS is a multisystemic phenotype characterized primarily by obesity, retinal degeneration, polydactyly, gonadal and renal malformation and behavioral and developmental problems. In addition, patients with BBS have been reported with a host of highly variable clinical features that range from reactive airway disease to psychiatric illness (for an in-depth discussion of the phenotype see 8–11). The disorder is relatively uncommon in Caucasian populations, with an estimated prevalence rate of 1 : 140 000–160 000 live births in North America and Europe (12,13), although higher incidence has been reported in the isolated populations of Newfoundland [1 : 13 000 (9)] and Kuwait [1 : 17 000 (14)]. The BBS phenotype represents a challenging genetic conundrum, since loss or dysfunction of a single protein is proposed to give rise to the distinct, multisystemic characteristics of the syndrome, including both progressive (such as retinal dystrophy and obesity) and structural (e.g. polydactyly and renal cysts) defects. Furthermore, BBS exhibits significant inter- and intrafamilial variability, which is also difficult to reconcile with a single-gene autosomal recessive model. Finally, despite an initial expectation that most BBS families would be assigned to the same locus, emerging mutational and statistical evidence has suggested significant genetic heterogeneity, with at least nine loci in the genome.

	GENE IDENTIFICATION IN BBS

TOP ABSTRACT INTRODUCTION THE GENETIC CHALLENGE OF... GENE IDENTIFICATION IN BBS SECOND-SITE MODIFICATION IN BBS EVALUATION OF TRIALLELIC... AN EVOLVING VIEW OF... SOME NEW GENETIC LESSONS TOWARDS A CELLULAR AND... CONCLUSIONS REFERENCES

 
After a 7 year hiatus between the mapping of the first BBS locus, BBS2 (15), and the cloning of the first gene, BBS6 (16,17), significant progress has been made in the last 3 years in elucidating the genetic basis of BBS. At present, there are six known BBS genes (Table 1). Two more loci, BBS3 (18) and BBS5 (19) have been mapped and genetic/mutational data in large cohorts indicate the presence of at least one more locus, since numerous families harbor no mutations at the six known genes and can be excluded from all eight loci by haplotype analysis (20–22). Importantly, most of the known loci harbor pathogenic mutations in a small percentage of BBS families (Fig. 1). Even BBS1, considered initially to be the major locus for the syndrome, with an expected contribution of 40–50% (23–25), is only mutated in 20–25% of caucasians and rarely in Bedouins, one of the major ethnic groups with high BBS incidence (26). As such, it is likely that either another major BBS locus remains at large or, more challenging, that the remaining >50% of BBS is distributed among a large number of genes, each of which contributes a modest percentage to the BBS mutation pool.

View this table: [in this window] [in a new window]   Table 1. The known BBS genes and their products

 

View larger version (25K): [in this window] [in a new window]   Figure 1. Contribution of the eight known BBS loci to BBS. Families with three mutations were assigned to a primary locus (the one with two mutations). The contribution of BBS3 and BBS5 was estimated from genotype data only, since no gene is yet known.

 

	SECOND-SITE MODIFICATION IN BBS

TOP ABSTRACT INTRODUCTION THE GENETIC CHALLENGE OF... GENE IDENTIFICATION IN BBS SECOND-SITE MODIFICATION IN BBS EVALUATION OF TRIALLELIC... AN EVOLVING VIEW OF... SOME NEW GENETIC LESSONS TOWARDS A CELLULAR AND... CONCLUSIONS REFERENCES

 
Both the significant genetic heterogeneity and clinical variability in BBS suggest that second-site genetic modification is highly likely, whereby mutations at a second gene might modulate the penetrance and/or expressivity of recessive mutations at a primary locus. What is more surprising, however, is that different BBS genes now appear capable of assuming either a causal or a modifying role in different families, potentially creating a novel paradigm of disease transmission in humans. The first indirect evidence for this phenomenon arose after the cloning of the first BBS gene, BBS6 (16,17). Detailed mutational and haplotype analyses in a large, multiethnic cohort revealed two types of potential deviations from pure Mendelian disease segregation models. First, in most families with BBS6 mutations, a second mutant allele could not be identified, despite direct dye–primer sequencing of the entire BBS6 cDNA (27). This raised the possibility that there was either a high frequency of a mutation type undetectable by the methodology (such as large deletions, control element disruptions, etc.) or that BBS6 might participate in complex inheritance. Second, and more intriguingly, a single heterozygous A242S mutation was found in one consanguineous family from Newfoundland (27) that had been predicted previously by haplotype analysis to map to BBS2 (28). This variant was unlikely to be benign, not least because it had been associated previously in the homozygous state with the phenotypically related McKusick–Kaufman syndrome (MKS) (29). Importantly, both the affected and unaffected siblings had identical haplotypes on both chromosomes across a 5 cM region centered around BBS6, indicating that if a second mutation was present at this locus, both sibs would have to have inherited it, even though one of them was both phenotypically normal and well beyond the mean age of onset of the disorder. A more parsimonious interpretation was that the A242S allele might interact genetically with mutations at another BBS locus (predicted in this instance to be BBS2). This hypothesis was tested directly upon the positional cloning of BBS2 (30) by screening the same cohort irrespective of previously ascertained linkage or mutational information. Four pedigrees were identified harboring likely pathogenic alterations in both BBS2 and BBS6, including the aforementioned family from Newfoundland, in which the affected, but not the unaffected sib, harbored a homozygous Y24X nonsense mutation in BBS2 (31). In a second outbred Caucasian family, both the affected and an unaffected sib were compound heterozygous for two nonsense BBS2 mutations; only the affected sib, however, carried an additional heterozygous nonsense mutation in BBS6. Based on these data, a new type of second-site modification was proposed, termed triallelic inheritance, whereby three mutant alleles at two loci were necessary for pathogenicity (31).

	EVALUATION OF TRIALLELIC INHERITANCE ACROSS KNOWN BBS GENES

TOP ABSTRACT INTRODUCTION THE GENETIC CHALLENGE OF... GENE IDENTIFICATION IN BBS SECOND-SITE MODIFICATION IN BBS EVALUATION OF TRIALLELIC... AN EVOLVING VIEW OF... SOME NEW GENETIC LESSONS TOWARDS A CELLULAR AND... CONCLUSIONS REFERENCES

 
Subsequent to the discovery of triallelic inheritance, screening of BBS6 in an independent cohort revealed a marked excess of families with one identifiable BBS6 mutation (five families) as opposed to two recessive mutations (two families). However, no bona fide triallelic combinations were identified, suggesting that BBS6 mutations might interact genetically with other loci (32). The cloning of a third BBS gene, BBS4 (33), provided some evidence that triallelic participation of mutant alleles was not restricted to BBS2 and BBS6 since single, heterozygous, likely pathogenic mutations were found in three families (34). Intriguingly, in a fourth consanguineous family of Kurdish descent, the affected individual carried homozygous mutations in both BBS2 (T558I) and BBS4 (A364E), whereas both the mother and an unaffected brother carried three mutant alleles (34).

Cloning of the fourth BBS gene, BBS1 and analysis of the transcript for complex inheritance, however, suggested that triallelism might not be a ubiquitous phenomenon in BBS. Families with BBS1 mutations inherited the trait in a recessive fashion, although a second causal mutation could not be found in a small proportion of sibships (35,36). In agreement with these data, Fauser and colleagues reported complex inheritance in BBS2 and BBS4 but not BBS1 in a cohort of 21 unrelated patients (22). However, the cloning of BBS7 contradicted these findings, since a heterozygous E237K mutation in BBS1 segregated with the disease in a Hispanic family that also carried a homozygous T211I mutation in BBS7 (21). Analysis of a larger cohort of 259 independent families from diverse ethnic backgrounds provided several lines of evidence that BBS1 participates in triallelism. These included the identification of six families with two BBS1 mutations and a third mutation at another BBS locus and two families in which an unaffected parent is homozygous for the M390R mutation (26), the most common BBS1 variant in Caucasians (35).

	AN EVOLVING VIEW OF ALLELE CONTRIBUTION TO TRIALLELIC INHERITANCE

TOP ABSTRACT INTRODUCTION THE GENETIC CHALLENGE OF... GENE IDENTIFICATION IN BBS SECOND-SITE MODIFICATION IN BBS EVALUATION OF TRIALLELIC... AN EVOLVING VIEW OF... SOME NEW GENETIC LESSONS TOWARDS A CELLULAR AND... CONCLUSIONS REFERENCES

 
Comparison of the relative frequency of documented triallelism (three mutations) or predicted triallelism (two mutations in asymptomatic relatives or one mutation in a family excluded by linkage) in each BBS gene shows marked differences between loci (Fig. 2A). From all the data available to date, BBS2 and BBS6 participate most frequently in triallelic combinations. In contrast, mutations in BBS1 seem to suffice to cause disease in more than 80% of BBS1 patients, which might explain in part the contradictory data on the involvement of BBS1 in triallelic inheritance. At present, only the recently identified BBS8 locus has not yet been implicated in such genetic phenomena (20), although this might reflect the small number (three) of pedigrees associated to date with BBS8.

View larger version (20K): [in this window] [in a new window]   Figure 2. Analysis of triallelic mutations. (A) Bar graph depicting the proportion of families manifesting recessive or oligogenic inheritance (contributing either one or two mutations) per locus. None of the three families with BBS8 mutations participates in triallelic inheritance. (B) Mutation type combinations in triallelic inheritance. Mutations were classified broadly as nonsense (N), missense (M), splice (S) or unknown (U). The latter indicate instances in which an unaffected parent or unaffected sib carries two mutations at a single locus, but a third allele has not yet been identified.

 
The types of mutations associated to date with triallelism are also beginning to offer some functional clues. Even though there are relatively few examples available, it is becoming evident that combinations of three bona fide complete loss of function alleles are rare, with only one documented example of three nonsense alleles being required for pathogenesis (involving BBS2 and BBS6). The remaining triallelic combinations consist primarily of two or three missense mutations (Fig. 2B). This raises the challenge of determining the pathogenic potential of missense alleles.

Historically, the segregation of a candidate variant with the disorder has been considered a strong indicator of pathogenicity. This criterion have also been used in the evaluation of potential triallelic mutations, a valid approach under a causality model, where a third mutant allele is assumed to be necessary for the manifestation of disease. However, segregation of triallelic mutations in BBS families, coupled with phenotypic and in vitro analyses of the mutant protein products has indicated that some mutations may affect the severity of a recessive phenotype, thereby expanding the model of triallelic inheritance to encapsulate the modification of both penetrance and expressivity (37).

In three BBS families, some, but not all patients were reported to have inherited a third pathogenic allele, which correlated in each case with increased severity of the disease. Inter- and intrafamilial phenotypic variance have been documented extensively for BBS (8,9,11), complicating any such phenotype–genotype correlations. However, one of the three families, PB009, harbors a homozygous M390R mutation in BBS1, in addition to a heterozygous L349W change in BBS2 which segregates with an earlier age of onset of the retinal phenotype (Fig. 3). It was thus possible to investigate the variance in age of onset of retinopathy, one of the more consistent aspects of the BBS phenotype, in multiple recessive families with a BBS1 M390R genotype and compare the variance with that of the family with the additional BBS2 mutation. Surprisingly, the mean difference in age of onset in recessive M390R families was only 3 years, compared with a difference of 19 years observed in the triallelic sibship (37).

View larger version (26K): [in this window] [in a new window]   Figure 3. Not all second-site modification events in BBS are causal. In each of the two families shown, a third mutation in BBS6 and BBS2, respectively, correlates with a more severe phenotype, as depicted underneath each patient. Fs=frameshift (1650°C); MR=mental retardation; RP=retinitis pigmentosa; SNB=stationary night blindness.

 
Similar phenomena were observed in the other two families, with BBS1 and BBS6 as the second-site modifier. For example, in family AR768, the BBS1 mutation, a splice junction mutation predicted to give rise to a null allele by nonsense-mediate decay, correlated with developmental delay in early infancy, whereas the BBS6 T325P missense mutation correlated with increased severity of several aspects of the phenotype including obesity, mental retardation and developmental delay (Fig. 3). Intriguingly, in vitro studies in HeLa cells suggested that this variant might have severe consequences to the protein function, since epitope-tagged overexpressed BBS6 constructs harboring the proline residue formed insoluble cytoplasmic precipitates (37).

Based on these examples, a gradient model has been proposed for BBS, transforming the phenotype from a monogenic to a quantitative trait, with the onset and severity of the disease being modulated by additional alleles, the number and relative contribution of which is unclear. This model is consistent with current ideas of disease causality, whereby penetrance, expressivity and epistasis are partial representations of a continuum of genetic influence (38,39).

	SOME NEW GENETIC LESSONS

TOP ABSTRACT INTRODUCTION THE GENETIC CHALLENGE OF... GENE IDENTIFICATION IN BBS SECOND-SITE MODIFICATION IN BBS EVALUATION OF TRIALLELIC... AN EVOLVING VIEW OF... SOME NEW GENETIC LESSONS TOWARDS A CELLULAR AND... CONCLUSIONS REFERENCES

 
Triallelic inheritance and other forms of second-site modification will probably require the adjustment of the traditional ways of evaluating candidate genes. First, the common practice of excluding a family from additional screening once a ‘causative’ mutation has been identified will probably lead to the loss of genetic interaction data. This is especially true in genetically heterogeneous traits like BBS. It is perhaps intuitively obvious that multiple genes that lead to the same phenotype are strong candidates for second-site modification, yet this possibility is frequently ignored.

The ascertainment of candidate oligogenic mutations can also be challenging. First, the traditional criterion that bona fide mutations should not be present in control chromosomes, the number of which is dictated usually by the population incidence of the disease, can no longer be applied. Unless some alleles involved in oligogenic inheritance have an elevated frequency in the general population, the chance of an individual inheriting three or more mutations at the same time would be small, which is not the case. For instance, the prevalence of the common M390R mutation in BBS1 in Caucasians is 1 : 325, compared with an expected frequency of 1 : 1000–2000 under a recessive model (26).

Finally, the segregation of a variant can also lead to an underappreciation of the effect of the allele on the phenotype. Under a monogenic model, several of the mutations seen in the BBS genes would have been discarded as benign (including a splice junction mutation in BBS1), whereas an epistatic hypothesis has provided a more parsimonious interpretation of these data (37). Modeling such genetic interactions can be challenging, with a real danger of both over- and under-interpreting mutational data. Such endeavors are likely to be facilitated by the development of cellular data and biochemical assays that can test directly the effect of a variant on a particular gene, its product and the pathway(s) in which it functions.

	TOWARDS A CELLULAR AND BIOCHEMICAL UNDERSTANDING OF TRIALLELISM

TOP ABSTRACT INTRODUCTION THE GENETIC CHALLENGE OF... GENE IDENTIFICATION IN BBS SECOND-SITE MODIFICATION IN BBS EVALUATION OF TRIALLELIC... AN EVOLVING VIEW OF... SOME NEW GENETIC LESSONS TOWARDS A CELLULAR AND... CONCLUSIONS REFERENCES

 
Despite significant progress in elucidating the genetic basis of oligogenic disorders, the translation of genotypic data to cellular paradigms remains largely elusive. Direct interaction models have emerged from studying the biochemical properties of ROM1 and RDS, which interact genetically to cause digenic retinitis pigmentosa (40) and whose protein products form tetramers (41–43). Other pairs of genetic interactions have proven to be underlined by similar relationships, such as the receptor–ligand pairings of JAG1 with NOTCH2 in Allagille syndrome (44) and RET-GDNF in Hirschsprung disease (45; see 2 for a more detail discussion of these models).

Initial cellular studies have indicated that the BBS proteins might play a role in the function of the pericentriolar region, since two BBS proteins, BBS4 and BBS8, were shown to localize specifically to the basal bodies and centrosomes of different cell types (20). Furthermore, the C. elegans orthologs of BBS1, BBS2, BBS7 and BBS8 were also shown to be expressed specifically in the ciliated dendritic endings of sensory neurons, raising the possibility that dysfunction of the basal body in ciliated cells might underlie several aspects of the phenotype (20). Given that there are no discernible differences between the phenotype caused by mutations at each of the known BBS genes, it is not surprising that the BBS proteins are converging to a common set of cellular functions and appear to be co-expressed (at least in lower organisms) in the same cell types. What is of greater genetic relevance, however, is that each of BBS4 and BBS8 interacts with the same pericentriolar protein, PCM1 (20), even though the stoichiometry of the interaction remains to be resolved. At present, there is no evidence of direct interaction between BBS4 and BBS8, or indeed any BBS protein pair (our unpublished data), suggesting that a direct complex model akin to ROM1-RDS, JAG1-NOTCH2 and others is unlikely. Rather, the BBS proteins might participate in a multiprotein complex that becomes progressively compromised by the presence of additional mutations. Alternatively (or in addition) they might act sequentially to affect the same cellular process, such as the translocation of material to the pericentriolar region or the axoneme of the cilium.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION THE GENETIC CHALLENGE OF... GENE IDENTIFICATION IN BBS SECOND-SITE MODIFICATION IN BBS EVALUATION OF TRIALLELIC... AN EVOLVING VIEW OF... SOME NEW GENETIC LESSONS TOWARDS A CELLULAR AND... CONCLUSIONS REFERENCES

 
Elucidation of the genetic and cellular mechanisms that underlie second-site phenotypic modification is important for understanding oligogenic disease, and is also a useful modeling template for complex traits, where both the number of participating alleles and the contribution of stochastic factors pose significant obstacles. BBS is thus a useful study system for deciphering such interactions both at the genetic and the cellular level. Since the original report of triallelic inheritance, several unrelated phenotypes have been reported to manifest similar modes of disease transmission, including nephrotic syndrome (46), cortisone reductase deficiency (47), haemochromatosis (48) and familial hypercholanemia (49), indicating that this genetic phenomenon is not restricted to BBS. Emerging animal models suggest that the genetic interaction observed in some BBS patients might be recapitulated (50,51). These, together with biochemical studies of wild-type and mutant BBS proteins will be important tools for the dissection of the cellular basis of triallelism and the application of the lessons learned towards monogenic and complex traits alike.

	ACKNOWLEDGEMENTS

 
I thank the members of my laboratory for their thoughtful critique of this manuscript. This study was supported by a grant from the National Institute of Child Health and Development, National Institutes of Health HD04260.

	FOOTNOTES

 
^* To whom correspondence should be addressed: Tel: +1 4105026660; Fax: +1 4105020697; Email: katsanis{at}jhmi.edu

	REFERENCES

TOP ABSTRACT INTRODUCTION THE GENETIC CHALLENGE OF... GENE IDENTIFICATION IN BBS SECOND-SITE MODIFICATION IN BBS EVALUATION OF TRIALLELIC... AN EVOLVING VIEW OF... SOME NEW GENETIC LESSONS TOWARDS A CELLULAR AND... CONCLUSIONS REFERENCES

 

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