Autosomal dominant cone-rod dystrophy due to a missense mutation ...

Research report

Ophthalmic Genetics 1381-6810/00/ US$ 15.00 Ophthalmic Genetics – 2000, Vol. 21, No. 4, pp. 197-209 © Swets & Zeitlinger 2000

Ophthalmic Genet Downloaded from informahealthcare.com by Norwegian Knowledge Cntr Health Svcs on 03/08/12 For personal use only.

Accepted 2 July 2000

Autosomal dominant cone-rod dystrophy due to a missense mutation (R838C) in the guanylate cyclase 2D gene (GUCY2D) with preserved rod function in one branch of the family Marijke Van Ghelue1 Hans L. Eriksen2 Vesna Ponjavic3 Toril Fagerheim1 Sten Andréasson3 Kristina Forsman-Semb4* Ola Sandgren5 Gösta Holmgren4 Lisbeth Tranebjærg1 Departments of 1Medical Genetics and 2Ophthalmology, University Hospital Tromsø, Tromsø, Norway 3 Department of Ophthalmology, University Hospital Lund, Lund; 4Department of Clinical Genetics, University Hospital, Umeå; and 5Department of Clinical Sciences/Ophthalmology, University Umeå, Umeå, Sweden

Abstract We present the clinical and molecular genetic features of a large multi-generation Norwegian family with dominant cone-rod dystrophy. Ophthalmological evaluation including electroretinography showed cone dysfunction in younger patients, with rod dysfunction becoming apparent at more advanced stages of the disease. In one branch of the family, cone degeneration remained the only manifestation despite advancing age. Linkage analysis mapped the disease gene in this family to 17p12-p13, a chromosome region previously linked to cone-rod dystrophy in a Swedish family (CORD5). A maximum LOD score of 3.25 (θ = 0.00) for marker D17S1844 was obtained. Mutation analysis of the guanylate cyclase 2D gene (GUCY2D, MIM 600179, previously called RETGC1), located at 17p12-p13, showed a missense mutation (R838C) in exon 13, that co-segregated with the eye disease in the family. Our suspicion of the possibility of an interrelationship between the Swedish CORD5 family and the present family, both originating from Northern * Present address: Astra Zeneca R&D, Molecular Genetics, Mölndal, S-431 83 Sweden.

Autosomal dominant cone-rod dystrophy due to GUCY2D mutation

Correspondence and reprint requests to: Lisbeth Tranebjærg, M.D., Ph.D. Dept. of Medical Genetics University Hospital of Tromsø N- 9038 Tromsø Norway Tel: +47 776 45410 Fax: +47 776 45430 e-mail: [email protected] Acknowledgements: We wish to thank all of the family members for their dedicated participation in this study. The project was financially supported by the Odd Fellow Medical Research Foundation (LT), the Margit Thyselius

→

197

Scandinavia, initiated the linkage analysis in the Norwegian family. The R838C missense mutation was not, however, detected in the Swedish patients, strongly suggesting no relationship between these two families. The long-term ophthalmological evaluation in this large four-generation family, combined with the identification of the disease-causing mutation, provide critical information for refining the classification, prognosis, and genetic counselling of patients with cone-rod dystrophies.


Key words Cone-rod dystrophy; ERG; genetic linkage; GUCY2D; Norway; Sweden

Foundation, the Swedish Society of Medicine, and the Kronprinsessans Margaretas Minnesfond (VP, SA). The project was approved by the Regional Ethical Research Committee in Tromsø, Norway.

198

Introduction Inherited retinal dystrophies show considerable clinical and genetic heterogeneity and can be classified according to the type of retinal cell that first shows signs of the disease; this classification includes rod-cone dystrophies, cone-rod dystrophies, and cone dystrophies.1,2 The underlying pathogenesis for a large number of retinal dystrophies is still unknown.3-5 Cone-rod dystrophies have their onset in early life. They are characterized by impaired color vision, decreased visual acuity, and photophobia. The color vision impairment usually affects the red-green spectrum,6 but occasionally blue cone dysfunction may be involved.7 In contrast to X-linked red-green color vision defects, cone-rod dystrophy is a progressive disorder. Affected individuals lose color vision by the time visual acuity is reduced to 20/40. At more advanced stages of the disease, rod dysfunction occurs. Degeneration of the rods is associated with a more severe visual prognosis because of restricted visual fields and impaired night vision. Cone-rod dystrophy can be inherited as autosomal dominant,8 autosomal recessive,9,10 or X-linked recessive traits.11-13 Autosomal dominant cone-rod dystrophy shows genetic heterogeneity, and may be caused by mutations in the peripherin gene (RDS) at 6p21.214,15 or in a photoreceptor-specific homeobox gene (CRX) at 19q13.3-q13.4.16,17 The study of patients with retinal dysfunction in association with chromosomal abnormalities has identified possible loci for cone-rod dystrophy on chromosomes 6,17, and 18.18-21 Recently, the gene loci for cone-rod dystrophy in a Swedish (CORD5) and an American (CACD) family were linked to 17p.8,22,23 The gene for a retinal disorder (CORD6) was mapped to 17p12-p1324 in a British family. Subsequently, a missense mutation (2584G→C, E837D) in the guanylate cyclase 2D gene, GUCY2D, mapping to 17p12-13 was identified.25-27 In the same report, three additional unrelated cone-rod dystrophy patients were briefly presented with a missense mutation in the neighboring codon (2585C→T, R838C). Detailed ophthalmologic findings in that large family were recently published, and the mutation was re-evaluated to be E837D/R838S.26,27 Perrault et al.28 reported a cone-rod dystrophy family in which another complex mutational event had occurred, including three consecutive missense mutations in GUCY2D (2584G→C, E837D; 2585C→T, R838C; 2589C→T, T839M).28 The report of linkage to 17p in the Swedish CORD5 family prompted a linkage study in the present Norwegian pedigree because of the rare M. Van Ghelue et al.

nature of this ophthalmologic disease in two families from Northern Scandinavia.


Patients and methods patients A large four-generation family from the northern part of Norway was studied (Fig. 1). Twenty-two family members were affected, eleven of whom were examined in detail (Fig. 1). Thirty-four family members, comprising 16 clinically affected (including the 11 more extensively investigated patients) and 18 unaffected, were included in the molecular studies. After the identification of a mutation in the GUCY2D gene in the Norwegian family, we screened DNA from patients in the Swedish CORD5 family22 and DNA samples from 80 normal Norwegian individuals for the presence of the R838C missense mutation. ophthalmologic examinations Snellen visual acuity, slit-lamp examination, and ophthalmoscopy (after pupillary dilatation) were performed in 11 patients from three generations. Fundus photographs were also obtained (see Fig. 3). Color vision was examined using Farnworth D-15 panel. Kinetic perimetry was performed with a Goldmann perimeter (V4e and I4e white light test). The final rod threshold was measured, after 40 minutes of dark adaptation, with a Goldmann-Weeker adaptometer. The central and peripheral parts of the retina were examined, with the patients fixating an object straight-ahead, 40° nasally, and 40° temporally. The stimulus size was 56 mm in diameter. Full-field electroretinograms were recorded on the investigated patients using a Nicolet Compact Four analysis system (Nicolet Biomedical Instruments, Madison, WI, USA), as described previously.29 The normal range for blue light, red light, white light, and 30 Hz flickering white light responses was determined in 70 patients, who were referred to the Department of Ophthalmology in Lund for various reasons, but had no detectable eye disorder (Table 1). isolation of dna DNA was extracted from peripheral blood using standard methods. Blood samples were obtained from 16 affected fam-


Fig. 1. Pedigree of the family. The symbols o and ❍ indicate unaffected males and females, respectively; ■ ¦ and ● indicate individuals with ophthalmologically recognized cone dystrophy. A diagonal line across a pedigree symbol marks a deceased person. Individuals marked with an asterix (*) were examined with ERG. The age at the time of the ERG investigation is given below each individual. All individuals marked with a bar above the pedigree symbol were included in linkage analysis.

199


Patient ID

Age

Visual acuity

Blue single flash amplitude (µV)

Red single flash amplitude (µV)

White single flash amplitude (µV)

30 Hz flicker white amplitude (µV)

OD

OS

OD

OD

OS

OD

OS

OD

OS

OS

III:1

73

1/60

1/60

60

50

0

0

90

70

0

0

IV:1

46

6/60

6/60

50

40

10

0

90

90

0

0

IV:4

44

6/60

6/60

30

70

0

0

100

90

5

6

V:4

21

6/20

6/15

120

160

0

0

230

270

25

14

III:3

66

1/60

1/60

60

40

0

0

80

60

4

2

IV:7

43

6/60

2/60

30

30

0

0

40

50

0

0

V:7

11

6/30

*

70

*

20

*

120

*

23

*

III:5

59

3/60

4/60

110

100

0

0

140

160

9

11

IV:12

36

2/60

6/60

200

140

90

100

240

380

39

38

IV:14

33

6/60

6/60

110

160

0

90

160

230

10

13

IV:17

23

6/6

6/6

80

90

30

0

120

160

12

13

Mean (2 SD) normal controls N=70

166 (115)

87 (13)

315 (196)

63 (41)

*Visual acuity and ERG recordings were not obtained from the left eye of this patient.

table 1. Electroretinographic measurement values from patients affected with cone-rod dystrophy and from normal controls. OD and OS refer to the right, resp., the left eyes of the patients.

ily members, 10 unaffected members, and eight spouses for linkage and mutation analysis. pcr analysis of microsatellite markers Genotyping was performed using nine microsatellite markers mapping to 17p12-p13. PCR reactions were performed using either 33P dCTP incorporation or fluorescence-labeled primers. The amplicons were separated by denaturing polyacrylamide gel electrophoresis and visualized either by autoradiography or laser detection (ABI 377, Perkin-Elmer, Foster City, CA, USA). Primer sequences were as described by Genethon (http://www.genethon. fr). The order of the microsatellite markers was adopted from summary maps maintained by the Human Genetics Group, University of Southampton (http://cedar.genetics.soton.ac.uk/pub/chrom17/map.html). linkage analysis Data were collected and a two-point linkage analysis was performed using MLINK, a subprogram of the LINKAGE package 5.10. Cone-rod dystrophy was analyzed as an autosomal dominant trait, with five age-dependent liability classes, according to Bal-

200

M. Van Ghelue et al.


ciuniene et al.22 The penetrance was set to 0 at 40 years.22 The disease allele frequency was set to 0.0001. mutation analysis Exon 13 of GUCY2D was amplified using intronic primers, as described by Kelsell et al.26 Both strands of PCR products were sequenced on an ABI Prism 377 DNA sequencer using the Big Dye sequencing kit according to the manufacturer (PE Applied Biosystems, Warrington, UK). To investigate additional family members, amplified exon 13 products were digested with HhaI and analyzed on a 2% agarose gel. This analysis detects two different missense mutations, E837D and R838C. 26 Results visual acuity and refraction The patients complained of photophobia before the age of ten. The male patients (III:1, age 73; III:3, age 66; III:5, age 59) (Fig. 1) had visual acuity below 20/200 (Table 1). Their children (IV:1, age 46; IV:4, age 44; IV:7, age 43; IV:12, age 36; IV:14, age 33; IV:17, age 23 ) and grandchildren (V:4, age 21; V:7, age 11) had visual acuity better than 20/200. A refractive error was characteristic for all examined patients. Nine of 11 patients had a myopia ranging from -0.50 D to -13.25 D (median -5.50 D), and the remaining two patients had a hyperopia of +1.50 D and +4.50 D. In the majority of patients (9/11), the refractive error was combined with astigmatism up to +5.00 D (median +2.00 D). color vision All patients failed the Farnsworth D-15 panel and they all had a nonspecific axis of confusion. visual fields Two brothers in generation III (III:1, age 73; III:3, age 66) demonstrated a marked constriction of their visual fields as well as small scotomas (Fig. 2A,B). The third brother, patient III:5 (age 59), had a normal visual field associated with moderately large central scotomas (Fig. 2C). All other patients were younger than 46 years of age and had normal visual fields. dark adaptation threshold Only two out of 11 patients (III:3, age 66; IV:7, age 43) showed a pathologically elevated final rod threshold after 40 minutes of dark adaptation. The same two patients also had reduced rod responses on ERG testing (see below). The other nine patients, ranging in age from 21 to 46 years, had a normal final rod threshold. The threshold was defined as normal if it did not exceed a log light intensity of 103. fundus appearance Patients III:1 and III:3, their affected children IV:1, IV:4, IV:7, and the grandchild of III:3, V:7, had a similar fundus appearance. The patients belonging to the oldest generation (III:1, III:3, and III:5) had considerable central atrophic changes including the macular region, with a few large clumps of pigment near the border of Autosomal dominant cone-rod dystrophy due to GUCY2D mutation

201

202


A

B

C



the atrophic lesion. There was also peripapillar atrophy and normal appearing midperiphery. The patients in generation IV, including the descendants from III:1 and III:3, showed similar but less extensive changes. Examined patients in generation V had only a slight disruption of macular pigment (Fig. 3). Fundus photographs could not be obtained from patient III:5. His three affected children (IV:12, IV:14, and IV:17) had normal looking fundi with only minimal disruption of macular pigment, observable only with magnification (Fig. 3). electroretinography Patients III:1, IV:1, IV:4, V:4, III:3, IV:7, and V:7 had similar electroretinographic changes (Fig. 4, Table 1). Stimulation with dim blue light resulted in reduced amplitudes of the b-wave in two patients (IV:4, IV:7), who had rod responses lower than -2 SD below the mean of normal controls. Three patients (III:1, III:3, and IV:14) had rod responses at the lower normal limit. Two patients (V:4, V:7), at age 21 and 11 years respectively, had normal rod responses. Stimulation with dim red light in patients IV:1 and V:7 resulted in significantly reduced responses (Table 1). The combined responses from cones and rods obtained by stimulation with white light were moderately reduced in amplitude, except in one patient (V:4), in whom it was normal. The selective cone response, obtained by stimulation with 30 Hz flickering white light, was severely reduced in the older patients and could only be measured with computer averaging and a narrow band pass filter. The cone response was only slightly reduced in the younger patients. The implicit cone b-wave implicit was prolonged in all patients with measurable cone responses. Electroretinograms from patients III:5, IV:12, IV:14, and IV:17 had a different appearance. These patients belonged to a separate branch of the pedigree (Fig. 1). Selective rod responses as well as the combined cone and rod responses were normal. Stimulation with dim red light did not create any response in patient III:5 (age 59), while the younger patients belonging to this family branch had normal or subnormal responses (Table 1). Selective cone responses were easily measured without any need for computer averaging. The cone b-wave amplitude was moderately reduced, except in one patient (IV:12), in whom it was normal. The implicit time of the cone b-wave was prolonged in all patients. Generally, the younger patients showed a less marked reduction of amplitudes when compared to the older patients (Fig. 4, Table 1). The implicit time, however, was prolonged in the same range in members from all three generations. linkage analysis The cone degeneration in this family followed an autosomal dominant inheritance. Accordingly, a genetic model-dependent linkage analysis was performed. A maximum LOD score of 3.25 (θ = 0.00) was obtained with D17S1844 (data not shown). Patient IV:14, a 36-year-old woman, who definitely had cone-rod dystrophy, shared only one non-informative marker with the haplotype segregating with the disorder (data not shown). However, mutation analysis of GUCY2D revealed that she had the missense mutation (R838C) and thus represented a double recombinant, thereby reducing the power of the genetic linkage analysis. Autosomal dominant cone-rod dystrophy due to GUCY2D mutation

← Fig. 2. (A) Visual fields in patient III:1 and his affected children and grandchild (IV:1, IV:4, and V:4). Note the constriction of the visual fields in the oldest patient. (B) Visual fields in patient III:3 and his affected child and grandchild (IV:7 and V:11). Note the constriction of the visual fields in the oldest patient. (C) Visual fields in patient III:5 and his affected children (IV:12, IV:14 and IV:17). Note that III:5 had normal visual fields.

203

204




mutation analysis The retinal-specific guanylate cyclase gene (GUCY2D) became a candidate gene for cone-rod dystrophy in the present family, after the report by Kelsell et al.26 in which DNA sequencing of exon 13 from affected individuals identified a C→T transition at nucleotide 2585, leading to a triplet change from CGC to TGC and a missense mutation at codon 838 (R838C) (Fig. 5). This mutation abolishes a HhaI restriction site. The amino acid change involves a shift from a charged polar amino acid (arginine, R) to an uncharged polar amino acid with a sulfhydryl group (cystein, C). The mutation co-segregated with the disease in all thoroughly examined family members. We did not detect the R838C mutation in 160 normal alleles from 80 Norwegian controls. In addition, we analyzed DNA from patients from the Swedish CORD5 family for the presence of the R838C mutation. Neither the R838C nor E837D mutations were present in this family.22 Sequencing of exon 13 of GUCY2D did not reveal any other mutation in this exon. Moreover, no aberrant bands were detected in any of the 19 GUCY2D exons after screening using single-strand conformation polymorphism analysis (data not shown) Discussion The classification and prognosis of cone dystrophies have been complicated by the variable dysfunction of the rods.10,16,20,21,30 Ophthalmologic examination of the present family demonstrated a surprisingly high degree of variation in rod degeneration. One branch of the present family had exclusively cone dysfunction even at advanced stages of progression of the retinal disease. The brief clinical description of three unrelated patients with the R838C mutation26 does not allow a good comparison with patients in the present report. Patients III:1 and III:3 and their affected children had central atrophic lesions, which were also present in generation IV. The older patients also had constricted visual fields. Patient III:5 and his affected children, of generation IV, had an almost normal appearing fundus, normal visual fields, and dark adaptation threshold. There was only a mild reduction of the cone responses. Moreover, in the younger patients in this branch of the family, there was no detectable rod degeneration. Other patients belonging to the same family, however, showed both cone and rod degeneration. The initial affection of cones may be followed by rod degeneration as the disease progresses. The long-term follow-up over several generations allowed the recognition of a striking ophthalmological variation which might have been missed in a sporadic patient. In agreement with the findings of Gregory-Evans et al.,27 we found the early onset of photophobia and progressive cone-rod dysfunction. A striking difference, however, is the preserved rod function even at advanced stages of the eye disease in one branch of our family. The reason for this phenomenon is unclear. Protective unidentified factors are suspected. It is important to search for mutations in relevant genes as a supplement to clinical and ERG examinations.26-28 So far, only three cone dystrophy genes have been characterized. These genes include the peripherin/RDS gene,14,15,31 the photoreceptor-specific homeobox gene CRX,32 corresponding to CORD2,33 and guanylate cyclase 2D GUCY2D, corresponding to CORD6.26 Autosomal dominant cone-rod dystrophy due to GUCY2D mutation

← Fig. 3. Fundus photographs of examined patients. Left column shows the fundus appearance of patient III:1 and his affected children and grandchild The middle column shows the fundus photographs from patient III:3 and his affected child and grandchild. The right column shows the fundus appearance of the affected children of patient III:5. No fundus photography was available from III:5. Note that patients III:1 and III:3, as well as their affected children, had similar abnormalities of the central fundus, whereas the affected children of patient III:5 had a normal appearing fundus.

205


Fig. 4. Full-field electroretinograms (ERG) in cone-rod dystrophy-affected patients. The uppermost diagram shows a normal ERG. The ERGs from patient III:1 and his affected children and grandchild are shown below. Next follows ERGs from III:3 and his affected child and grandchild, and finally at the bottom ERGs from III:5 and his affected children. ERGs from III:1, III:3, and their descendants show moderately reduced rod responses and severely reduced cone responses in older patients. ERGs from patient III:5 and his affected children, however, show only slightly reduced rod and cone responses.

206



Four independent studies have mapped a disease gene associated with cone dystrophy to 17p.22-24 That region also contains a locus for Leber’s congenital amaurosis (MIM 204000) and central areolar choroidal dystrophy.33,34 Three genes in this region of chromosome 17 have been identified: guanylate cyclase 2D gene (GUCY2D ); retinal recoverin protein (RCV 1); and pigment epithelium-derived factor (PEDF), all of which are candidate genes for retinal dystrophies. Perrault et al.35 identified homozygosity for a missense mutation, 1617 T→C (F589S), in the GUCY2D gene in two inbred Arab Algerian families with autosomal recessive Leber’s congenital amaurosis. Recently, Kelsell et al.26 reported two different missense mutations in the guanylate cyclase gene 2D gene (GUCY2D) in dominant cone-rod dystrophy families. Mutation analysis demonstrated that the present family had a missense mutation (2585C→T, R838C) in exon 13 of GUCY2D, identical to the mutation identified in three unrelated conerod dystrophy patients reported by Kelsell et al.26 We did not find the missense mutation, R838C, in 160 normal Norwegian control chromosomes. A British four-generation family investigated by Kelsell et al.26 was initially reported to have the E837D missense mutation, although re-evaluation indicated a double mutation (E837D/R838S) due to a more complex mutational event.27 The mutation found in the present family is localized in the putative dimerization domain of the GUCY2D protein.35 Substitutions occurring in the dimerization domain most probably induce a steric change during dimer formation that affects the activity of the enzyme from both mutantmutant and normal-mutant dimers. The predicted loss of functional enzyme would result in a reduction in activity below the 50% level expected in heterozygotes for recessive null mutations. The consequent inability to regenerate cGMP might account for the extreme photophobia in patients of the CORD6 family and the present family.26 It appears that mutations in GUCY2D cause either autosomal recessive Leber’s congenital amaurosis or autosomal dominant cone-rod dystrophy, depending on the location of the mutation in the gene.26-28,35 Taking the present report into account, very similar ophthalmological abnormalities have been demonstrated in the six families reported so Autosomal dominant cone-rod dystrophy due to GUCY2D mutation

Fig. 5. Sequence analysis of exon 13 of GUCY2D gene from an unaffected (left) and an affected (right) individual, showing the 2585C→T transition (CGC→TGC) as indicated by the arrow.

207


far with missense mutations in the nucleotide stretch from nt 2584 to 2589 ( G CGC AC).26-28 It is conceivable that there is a mutational hot spot in that region and that disruption of this domain has significant influence on the function of the peptide.36 The present family represents the first extensive description of the ophthalmologic prognosis in patients with the R838C mutation in the GUCY2D gene. In the family with a compound missense mutation E837D/R838S in the same functional domain, a similar pattern with early cone degeneration and later rod affection was described. The three briefly mentioned patients with the same R838C missense mutation also had very similar ophthalmologic abnormalities, but no saving of rod function in any affected family members.26 Genealogical studies of the three families did not indicate a shared origin, but haplotyping of all four families would provide better clues in favor of either a founder chromosome or recurrent mutations in a stretch of DNA, apparently prone to mutate.26 We conclude that the present Norwegian family is very unlikely to be related to the previously CORD5 family from Sweden despite a similar ophthalmological phenotype and mapping of the disease gene to 17p.22 Additional studies are required to resolve whether this similarity is due to mutational or locus heterogeneity. Our results clearly indicate that present classification of retinal dystrophies should take into account molecular genetic investigations. The intriguing differences in ophthalmologic findings in different branches of the same extended family remain so far unexplained and may indicate that other, yet unidentified, modifying factors must be taken into account before a reliable prognosis can be predicted after thorough ophthalmological and molecular investigation. The increasing possibilities for mutation analysis will be of diagnostic benefit for patients with cone-rod dystrophy and other retinal disorders. References 1 Goodman G, Ripps H, Siegel IM. Cone dysfunction syndromes. Arch Ophthalmol 1963;70:214-231. 2 Krill AE, Deutman AF, Fishman M. The cone degenerations. Doc Ophthalmol 1973;35(1):1-80. 3 Moore AT. Cone and cone-rod dystrophies. J Med Genet 1992;29: 289-299. 4 Rosenfeld P, Dryja TP. Molecular genetics of retinitis pigmentosa and related retinal degenerations. In: Wiggs JL, editor. Molecular Genetics of Ocular Disease. New York: WileyLiss, 1995; 99-126. 5 Small KW. Molecular genetics of macular degeneration In: Wiggs JL, editor. Molecular Genetics of Ocular Disease. New York: Wiley-Liss, 1995; 127-137.

208

6 Weleber RG, Eisner A. Cone degeneration (‘bull’s eye dystrophy’s) and color vision defects. In: Newsome DA, editor. Retinal Dystrophies and Degeneration. New York: Raven Press, 1988;154(162):233-256. 7 Went LN, Van Schooneveld MJ, Oosterhuis JA. Late onset dominant cone dystrophy with early blue cone involvement. J Med Genet 1992;29: 295-298. 8 Small KW, Gehrs K. Clinical study of a large family with autosomal dominant progressive cone degeneration. Am J Ophthalmol 1996; 121:1-12. 9 Gouras P, Eggers HM, MacKay CJ. Cone dystrophy, nyctalopia and supernormal rod responses. A new retinal degeneration. Arch Ophthalmol 1983;101:718-724.


10 Yagasaki K, Jacobson SG. Cone-rod dystrophy. Phenotypic diversity by retinal function testing. Arch Ophthalmol 1989;107(5):701-708. 11 Van Everdingen JAM, Went LN, Keunen JEE, Oosterhuis JA. X-linked progressive cone dystrophy with specific attention to carrier detection. J Med Genet 1992;29:291-294. 12 Jacobson DM, Thompson HS, Bartley JA. X-linked progressive cone dystrophy. Clinical characteristics in males and female carriers. Ophthalmology 1989;96:885-895. 13 Bartley J, Geis C, Jacobson D. Xlinked progressive cone dystrophy maps between DXS7(L1.28) and DXS206(XJ1.1) and is linked to DXS 84(754). Cytogenet Cell Genet 1989; 51:959. 14 Nakazawa M, Kikawa E, Chida Y,


15

16

17

18

19

20

21

22

Tamai M. Asn244His mutation of the peripherin/RDS gene causing autosomal dominant cone-rod degeneration. Hum Mol Genet 1994; 3:1195-1196. Nakazawa M, Kikawa E, Chida Y, Wada Y, Shiono T, Tamai M. Autosomal dominant cone-rod dystrophy associated with mutations in codon 244 (Asn244His) and codon 184(Tyr184Ser) of the peripherin/RDS gene. Arch Ophthalmol 1996; 114:7278. Evans K, Fryer A, Inglehearn C, Duvall-Young J, Whittaker JL, Gregory CY, Butler R, Ebenezer N, Hunt DM, Bhattacharya S. Genetic linkage of cone-rod retinal dystrophy to chromosome 19q and evidence for segregation distortion. Nat Genet 1994;6(2):210-213. Gregory CY, Evans K, Whittaker JL, Fryer A, Weissenbach J, Bhattacharya SS. Refinement of the cone-rod retinal dystrophy locus on chromosome 19q. Am J Hum Genet 1994;55:1061-1063. Tranebjærg L, Sjö O, Warburg M. Retinal cone dysfunction and mental retardation associated with a de novo balanced translocation 1;6(q44;q27). Ophthalmic Paediatr Genet 1986;7(3): 167-173. McLeod DR, Fowlow SB, Robertson A, Samcoe D, Burgess I, Hoo JJ. Chromosome 6q deletions: a report of two additional cases and a review of the literature. Am J Med Genet 1990; 35(1):79-84. Warburg M, Sjö O, Tranebjærg L, Fledelius HC. Deletion mapping of a retinal cone-rod dystrophy: assignment to 18(q21.1). Am J Med Genet 1991;39:288-293. Kylstra JA, Aylsworth AS. Cone-rod retinal dystrophy in a patient with neurofibromatosis type 1. Can J Ophthalmol 1993;28:79-80. Balciuniene J, Johansson K, Sandgren O, Wachtmeister L, Holmgren G, Forsman K. A gene for autosomal dominant progressive cone dystrophy

23

24

25

26

27

28

29

(CORD5) maps to chromosome 17p12-p13. Genomics 1995;30:281286. Small KW, Syrquin M, Mullen L, Gehrs K. Mapping of autosomal dominant cone degeneration to chromosome 17p. Am J Ophthalmol 1996;121:13-18. Kelsell RE, Evans K, Gregory CY, Moore AT, Bird AC, Hunt DM. Localization of a gene for dominant cone-rod dystrophy (CORD6) to chromosome 17p. Hum Mol Genet 1997;4:597-600. Oliveira L, Miniou P, ViegasPequignot E, Rozet JM, Dollfus H, Pittler SJ. Human retinyl guanylate cyclase (GUC2D) maps to chromosome 17p13.1. Genomics 1994;22:478-481. Kelsell RE, Gregory-Evans K, Payne AM, Perrault I, Kaplan J, Yang R-B, Garbers DL, Bird AC, Moore AT, Hunt DM. Mutations in the retinal guanylate cyclase (RETGC-1) gene in dominant cone-rod dystrophy. Hum Mol Genet 1998;7(7):1179-1184. Gregory-Evans K, Kelsell RE, Gregory-Evans CY, Downes SM, Fitzke FW, Holder GE, Simunovic M, Mollon JD, Taylor R, Hunt DM, Bird AC, Moore AT. Autosomal dominant cone-rod retinal dystrophy (CORD6) from heterozygous mutation of GUCY2D, which encodes retinal guanylate cyclase. Ophthalmology 2000;107:55-61. Perrault I, Rozet JM, Gerber S, Kelsell RE, Souied E, Cabot A, Hunt DM, Munnich A, Kaplan J. A RETGC-1 mutation in autosomal dominant conerod dystrophy. Am J Hum Genet 1998;63(2):651-654. Andréasson S, Ponjavic V, Abrahamson M, Ehinger B, Wu W, Fujita R, Buraczynska M, Swaroop A. Phenotypes in three Swedish families with X-linked retinitis pigmentosa caused by different mutations in the RPGR gene. Am J Ophthalmol 1997; 124:95-102.


30 Berson EL, Gouras P, Gunkel RD. Progressive cone-rod degeneration. Arch Ophthalmol 1968;80(1):68-76. 31 Kohl S, Christ-Adler M, ApfelstedtSylla E, Kellner U, Eckstein A, Zrenner E, Wissinger B. RDS/ peripherin gene mutations are frequent causes of central retinal dystrophies. J Med Genet 1997;34(8):620-626. 32 Freund CL, Gregory-Evans CY, Furukawa T, Papaioannou M, Looser J, Ploder L, Bellingham J, Ng D, Herbrick J-A, Duncan A, Scherer SW, Tsui L-C, Loutradis-Anagnostou A, Jacobson SG, Cepko CL, Bhattacharya SS, McInnes RR. Cone-rod dystrophy due to mutations in a novel photoreceptor-specific homeobox gene (CRX) essential for maintenance of the photoreceptor. Cell 1997;91(4):543553. 33 Camuzat A, Dollfus H, Rozet J-M, Gerber S, Bonneau D, Bonnemaison M, Briard M-L, Dufier J-L, Ghazi I, Leowski C, Weissenbach J, Frezal J, Munnich A, Kaplan J. A gene for Leber’s congenital amaurosis maps to chromosome 17p. Hum Mol Genet 1995;4:1447-1452. 34 Hughes AE, Lotery AJ, Silvestri G. Fine localisation of the gene for central areolar choroidal dystrophy on chromosome 17p. J Med Genet 1998; 35(9):770-772. 35 Perrault I, Rozet JM, Calvas P, Gerber S, Camuzat A, Dollfus H, Chatelin S, Souied E, Ghazi I, Leowski C, Bonnemaison M, Le Paslier D, Frézal J, Dufier J-L, Pittler S, Munnich A, Kaplan J. Retinal-specific guanylate cyclase gene mutations in Leber’s congenital amaurosis. Nat Genet 1996; 14(4):461-464. 36 Dizhoor AM, Lowe DG, Olshevskaya EV, Laura RP, Hurley JB. The human photoreceptor membrane guanylyl cyclase, RetGC, is present in outer segments and is regulated by calcium and a soluble activator. Neuron 1994; 2(6):1345-1352.

209
