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Human Molecular Genetics Pages 1179-1184  

Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy
Introduction
Results
Discussion
Materials And Methods
   Isolation of DNA
   Mutation screening
Acknowledgements
Abbreviations
References

Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy

Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy

Rosemary E. Kelsell1, Kevin Gregory-Evans2, Annette M. Payne1, Isabelle Perrault3, Josseline Kaplan3, Ruey-Bing Yang4, David L. Garbers4, Alan C. Bird2, Anthony T. Moore5, David M. Hunt1,*

1Department of Molecular Genetics, Institute of Ophthalmology, University College London, Bath Street, London EC1V 9EL, UK, 2Department of Clinical Ophthalmology, Moorfields Eye Hospital, City Road, London EC1V 2PD, UK, 3Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U-393, Hôpital des Enfants-malades, 149 rue de Sèvres, 75743 Paris, Cedex 15, France, 4Howard Hughes Medical Institute and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75235-9050, USA and 5Department of Ophthalmology, Addenbrook's Hospital, Hills Road, Cambridge CB2 2QQ, UK

Received 2 March, 1998; Revised and Accepted 21 April, 1998

The dominant cone-rod dystrophy gene CORD6 has previously been mapped to within an 8 cM interval on chromosome 17p12-p13. The retinal-specific guanylate cyclase gene (RETGC-1), which maps to within this genetic interval and previously was implicated in Leber's congenital amaurosis, was screened for mutations within this family and in a panel of small families and individuals with various cone and cone- rod dystrophy phenotypes. A missense mutation (E837D) was identified in affected members of the CORD6 family, as well as a second missense mutation (R838C) in three other families with dominant cone-rod dystrophy. RETGC-1 is only the fourth gene to be implicated in cone-rod dystrophy and this is the first report of dominant mutations in this gene.

INTRODUCTION

Cone-rod dystrophies belong to a group of eye disorders, the chorioretinal dystrophies, that are the most common cause of inherited eye disease. Cone-rod dystrophy is characterized by the initial degeneration of cone photoreceptor cells, causing early loss of visual acuity and colour vision, followed by the degeneration of rod photoreceptor cells leading to progressive night blindness and peripheral visual field loss (1). The disease displays phenotypic heterogeneity, and recent genetic studies have implicated a number of different gene loci in its aetiology (2-4). However, as yet, mutations have only been identified in three genes, peripherin/RDS (5-8), CRX (9)and ABCR (10).

We have recently localized a gene for a dominant cone-rod dystrophy (CORD6) to an 8 cM interval on chromosome 17p12-p13 (3) that includes the retinal-specific guanylate cyclase gene (RETGC-1) (11). Mutations in this gene have been shown to be responsible for Leber's congenital amaurosis (LCA1) (12,13), the most severe form of inherited retinopathy with total blindness or greatly impaired vision recognized at birth or in early infancy. These mutations show a recessive pattern of inheritance with no reported heterozygous effects.

A number of examples have now been reported where different mutations in the same gene result in clinically distinct inherited retinopathies (5-8,14-19) and where the pattern of inheritance also differs (20,21). It is possible, therefore, that a dominant phenotype is associated with mutations in RETGC-1, and we have, accordingly, screened the original CORD6 family and a panel of small families and individuals with various cone and cone-rod dystrophy phenotypes for RETGC-1 mutations.

RESULTS

The pedigree of the four generation British CORD6 family in which the disease phenotype has been mapped to chromosome 17p12-p13 (3) is shown in Figure 1A. The first six individuals on the left side of the pedigree are additional members of the family who were recruited subsequent to its first publication. Cone-rod dystrophy in this family displays an early onset, with loss of central vision reported before 7 years of age and peripheral field loss by the fourth decade. A notable feature is marked photophobia, particularly when dark-adapted. Fundoscopy shows a `bull's eye' maculopathy early in the disease (Fig. 2A), with later involvement of the peripheral retina. Electroretinography showed no detectable cone responses early in disease, with progressive abnormality of rod responses appearing later. A detailed clinical description of the disease in this and other families presented in this report will be given elsewhere (K. Gregory-Evans et al., in preparation).


Figure 1. Co-segregation of the dominant G->C missense mutation in affected members of the CORD6 pedigree. (A) Pedigree of the CORD6family. (B) Co-segregation of the abolished HhaI site in exon 13 with affected individuals of the family. Affected individuals exhibit the larger undigested DNA product (mutated allele) as well as the smaller digested doublet (bands not resolved on the gel) (normal allele). Unaffected individuals show only the doublet. (C) Reverse sequence of an unaffected individual (left) and an affected individual (right). The heterozygous G->C missense mutation in exon 13 at nucleotide 2584 (E837D) is indicated by an arrow.
Figure 2. (A)Colour fundus photography of right and left eyes of a 48-year-old male from family 1 (CORD6) showing strong bilateral macular atrophy. (B) Colour fundus photography of right and left eyes of a 45-year-old female from family 2 (leftmost in Fig. A) showing similar macular atrophy.

Direct sequence analysis of all 18 coding exons of RETGC-1 in the CORD6 family revealed a heterozygous alteration in exon 13 at nucleotide 2584 (G->C) in 10 affected individuals (Fig. 1A and C) that was absent in 10 unaffected individuals of the family. This sequence change results in the abolition of an HhaI restriction endonuclease site that co-segregates with all affected individuals (Fig. 1B). The loss of HhaI was not observed in any of the unaffected individuals within the pedigree, nor in >600 normal chromosomes from other British individuals (data not shown). The absence of the mutation in such a large number of normal chromosomes would imply that the G->C transversion is the disease-causing mutation. However, an alternate possibility is that this sequence alteration represents a very rare non-pathological polymorphism.


Figure 3. The dominant C->T missense mutation in affected members of the three other cone-rod dystrophy families. (A) Pedigrees of the three families, with numbers indicating the individuals for whom DNA samples were available for molecular analysis. (B) Co-segregation of the abolished HhaI site in exon 13 with the affected individuals of the families (see legend to Fig. 1B). (C) Sequence of an unaffected individual (left) and an affected individual (right). The C->T heterozygous missense mutation in exon 13 at nucleotide 2585 (R838C) is indicated by an arrow.

Approximately 50 additional small families or individuals with various cone or cone-rod dystrophy phenotypes were screened by HhaI digestion of exon 13. Heterozygous loss of this site was detected in affected individuals in the three additional cone-rod dystrophy families shown in Figure 3. Sequence analysis of all affected individuals revealed that the loss of the HhaI site in this case was the result of a C-> T transition at nucleotide 2585. Affected individuals in these families, although aware of poor vision in bright light from an early age, suffered loss of central vision in the late second or third decade, rather later therefore than in the CORD6 family. The fundus appearance of affected members of these families was very similar to the CORD6 phenotype (Fig. 2B). Electrophysiological testing revealed marked loss of photopic function by the mid-teens, with scotopic function becoming compromised later. Genealogical studies have failed to show that these families form a single large pedigree.

The G->C transversion in the CORD6 family results in the replacement of glutamate by aspartate at codon 837 (E837D) whereas the C->T transition in the other three families results in the replacement of arginine by cysteine at codon 838 (R838C). These amino acid changes occur within the putative dimerization domain of the RETGC-1 protein (22) (Fig. 4A). RETGC-1 is a member of a subgroup of membrane-bound guanylate cyclases which are expressed specifically in sensory tissues (24). Alignment of part of this domain (from codon 809 to 871) from human RETGC-1 and six other members of the subgroup shows that both Glu837 and Arg838 are fully conserved (Fig. 4B). The predicted secondary structure of this region of the protein is that of an [alpha]-helix and the cysteine substitution is likely to cause a steric change. Although the aspartate substitution in the CORD6 family is unlikely to destroy the formation of the predicted [alpha]-helix, the conservation of this amino acid at this site indicates that it may be critical for the proper functioning of the enzyme.


Figure 4. Structural and functional organization of guanylate cyclase. (A) Intron-exon structure of the human RETGC-1 gene with protein domains shown underneath. E837D denotes the location of the G->C missense mutation within exon 13 in the CORD6 family. R838C denotes the location of the C->T missense mutation within exon 13 of the other three cone-rod dystrophy families. Both are situated within the putative dimerization domain of the protein. nt460delC, nt693delC and F589S denote published mutations which have been identified in exons 2 and 8 in three families with Leber's congenital amaurosis (12). (B) Amino acid sequence alignment of human RETGC-1, rat GC-E (29), human RETGC-2 (34), rat GC-F (29), bovine ROS-GC (36), mouse GC-E (29) and rat GC-D (37). Codon 894 (numbering from the start of translation) denotes the end of the putative dimerization domain and the start of the catalytic domain of the protein. Asterisks identify residues of identity, and the [alpha]-helical domain within this region is also indicated. Residues Glu837, which is replaced by Asp in the CORD6 family, and Arg838, which is changed to Cys in the three other cone-rod dystrophy families, are indicated by the arrows.

DISCUSSION

Guanylate cyclase is a critical component in the recovery process of phototransduction in the vertebrate retina. In both rod and cone photoreceptors, photoactivated rhodopsin stimulates cGMP phosphodiesterase activity via GTP/GDP exchange on the G protein transducin, with consequent hydrolysis of cGMP and the closure of cGMP-gated channels. The entry of Ca2+ through the channel is thereby blocked, but export continues, resulting in a hyperpolarization of the plasma membrane (25). In the recovery phase, the drop in Ca2+ concentration (26) leads to a stimulation of membrane-bound guanylate cyclase production via the activation of guanlylate cyclase-activating protein (27). The catalytic conversion by the cyclase of GTP to cGMP results in the restoration of cGMP levels to the dark state and the re-opening of the gated channels (28). Two isoforms of guanylate cyclase, encoded by separate genes, have been identified in the mammalian retina (29). The active cyclase is a dimer (30,31) and although both are expressed in cone and rod photoreceptors, homomers between two identical subunits are formed preferentially in vivo (31). In the human retina, the two isoforms are encoded by RETGC-1 and RETGC-2, with RETGC-1 showing a higher levels of expression in cone than in rod cells (32-34). Since recessive mutations in RETGC-1 are responsible for the severe blinding condition of LCA1, it is unlikely that RETGC-2 can compensate for the loss of RETGC-1 activity.

We have identified two new mutations in the RETGC-1 gene that are associated with dominant cone-rod dystrophy, a E837D substitution that co-segregates with the dystrophy in the CORD6 family (3), and a R838C substitution that is present in three additional small families with cone-rod dystrophy. Neither mutation is present in >600 normal chromosomes, indicating that the cone-rod dystrophies in the respective families appear to be caused by these mutations. However, until functional studies are undertaken, we cannot entirely rule out the possibility that these mutations are very rare non-pathological polymorphisms. The base changes are in adjacent nucleotides in the gene, suggestive of a mutation-prone region, although this will require the screening of additional cone-rod dystrophy patients to determine whether this is indeed the case.

The region of the gene where both mutations are located encodes the putative dimerization domain of the RETGC-1 protein (23). Significantly, recessive LCA1 mutations (12,13), although found throughout the catalytic and kinase-like domains, are notably absent from this region. This suggests a possible mechanism for the dominant action of the two cone-rod mutations. Substitutions in the dimerization domain may result in a steric change during dimer formation that affects the activity of both mutant-mutant and mutant-normal dimers. The resulting loss of functional enzyme would result in a reduction in activity below the 50% level expected in heterozygotes for recessive null mutations. Such a dominant-negative effect has already been demonstrated by in vitro mutagenesis in the rat orthologue, GC-E (31). The consequent inability to regenerate cGMP would account for the extreme photophobia exhibited by affected members of the CORD6 family.

To date, only three other genes have been implicated in cone-rod dystrophy, peripherin/RDS (5-8), CRX (9) and ABCR (10). The RETGC-1 mutations are the first examples therefore of cone-rod dystrophy arising from structural changes in one of the enzymic components of the phototransduction process. However, the recent identification of a dominant mutation in the activator of retinal guanylate cyclase (GUCA1A) in dominant cone dystrophy (35) confirms the importance of a normal recovery phase in phototransduction to the maintenance of photoreceptor function.

MATERIALS AND METHODS

Isolation of DNA

DNA was extracted from EDTA-blood samples with a Nucleon II kit (Scotlab Bioscience). Genotyping was performed as described previously (22).

Mutation screening

Thecoding exons of the RETGC-1 gene were amplified using the intronic primers and annealing temperatures essentially as described (12), except that the 5[prime] portion of exon 2 was amplified with primer pair 5[prime]-TTACGGGGAGAACCCTAGGGGAGGCCG-3[prime] (forward) and 5[prime]-AGAGAAGATGGGGTCGCAAG-3[prime] (reverse) at an annealing temperature of 68°C, the middle portion of exon 2 with primer pair 5[prime]-CTCTCCGCCGTGTTCACGGT-3[prime] (forward) and 5[prime]-GCGATCCCGGCTTCTTCGGC-3[prime] (reverse) at 60°C, and the 3[prime] portion of exon 2 with primer pair 5[prime]-TCCGGTGAACCCTGCGGCCT-3[prime] (forward) and 5[prime]-TGCCGGCAGGACCAGCCGAC-3[prime] (reverse) at 68°C. A different forward primer (5[prime]-GCATTCTGGGACAGTGAGCC-3[prime]) was used for exon 8. Exons 6 and 7 were amplified at an annealing temperature of 55°C, exon 11 at 68°C, exon 15 at 58°C and exon 17 at 68°C. PCR reactions (25 or 50 µl) were performed, each containing 1.5 mM MgCl2, 0.4 mM each primer, 200 mM each dNTP, 16 mM (NH4)2SO4, 67 mM Tris-HCl pH 8.8, 0.01% Tween-20 and 1 U of Taq DNA polymerase (Bioline). After an initial denaturation for 3 min at 94°C, 30 cycles of denaturation at 94°C for 1 min, annealing at the exon-specific temperature for 1 min, and extension at 72°C for 1 min were performed, with a final extension at 72°C for 3 min. Each exon was sequenced directly in both directions, using the PCR generation primers. Sequencing was performed using AmpliTaq FS polymerase cycle sequencing with dye-labelled dideoxyterminators, and the products were visualized on an Applied Biosystems Model 373 DNA Sequencer. Products obtained for exon 13 were digested with HhaI and analysed on 2% agarose gels.

ACKNOWLEDGEMENTS

We thank the family members for their cooperation in this study. We are also grateful to Dr Martin Warren, Dr Cheryl Gregory-Evans, Dr Susan Downes and Dr David Kelsell for helpful discussions. This work was supported by a grant from the Wellcome Trust (grant no. 041905).

ABBREVIATIONS

ABCR, retina-specific ABC transporter gene; bovine ROS-GC, bovine rod outer segment guanylate cyclase gene; CORD6, cone-rod dystrophy 6 gene; CRX, photoreceptor-specific homeobox gene; GUCA1A,gene encoding theactivator of retinal guanylatecyclase; LCA1, Leber's congenital amaurosis gene 1; mouse GC-E, mouse guanylate cyclase E; peripherin/RDS, peripherin retinal degeneration slow gene; rat GCE-D, GC-E and GC-F, rat guanylate cyclases D, E and F, respectively; RETGC-1 and RETGC-2, human retinal guanylate cyclase genes 1 and 2, respectively.

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*To whom correspondence should be addressed. Tel: +44 171 608 6820; Fax: +44 171 608 6863; Email: d.hunt@ucl.ac.uk

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