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Localization of CSNBX (CSNB4) Between the Retinitis Pigmentosa Loci RP2 and RP3 on Proximal Xp Alison J. Hardcastle,* Zoe K. David-Gray* Marcelle Jay,-f Alan C. Bird,^; and Shomi S. Bhattacharya* Purpose. Proximal Xp harbors many inherited retinal disorders, including retinitis pigmentosa (RP) and congenital stationary night blindness, both of which display genetic heterogeneity. X-linked congenital stationary night blindness (CSNBX) is a nonprogressive disease causing night blindness and reduced visual acuity. Distinct genetic loci have been reported for CSNBX at Xp21.1, which is potentially allelic with the RP3 gene, and at Xpll.23, which is potentially allelic with the RP2 gene. The study to identify the RP2 gene led to an extended study of families with potentially allelic diseases that include CSNBX. Methods. Haplotype analysis of a family diagnosed with CSNBX was performed with 17 polymorphic markers on proximal Xp covering previously identified loci for CSNBX and XLRP. Twopoint and multipoint lod scores were calculated. Results. Informative recombinations in this family define a locus for CSNBX (CSNB4) with flanking markers DXS556 and DXS8080 on Xpll.4 to Xpll.3, an interval spanning approximately 5 to 6 cM. A maximum lod score of 3.2 was calculated for the locus order DXS5561 cM-(CSM*4-DXS993)-2 cM-DXS1201. Conclusions. The results describe a new localization for CSNBX (CSNB4) between the /?P2and RP3\oc\ on proximal Xp. CSNB4 is not allelic with any previously reported XLRP loci; however, the interval overlaps the locus reported to contain the cone dystrophy (C0D1) gene, and both diseases are nonrecombinant with DXS993. Because mutations in the RPGR gene to date account for disease in only a small proportion of RP3 families, the possibility that this new locus (CSNB4) also segregates with an as yet unidentified XLRP locus cannot be excluded. Invest Ophthalmol Vis Sci. 1997;38:2750-2755. C^ongenital stationary night blindness (CSNB) denotes a series of nonprogressive retinal disorders inherited in an autosomal dominant (adCSNB), autosomal recessive (arCSNB), and an X-linked (CSNBX) form. CSNBX is associated with myopia and decreased visual acuity and is believed to result from defective neurotransmission between photoreceptors and bipolar cells.1"3 Night blindness is also a well characterized early clinical feature of the progressive degenerative retinal disease retinitis pigmentosa (RP), and the func- From the * Departments of Molecular Genetics and f Clinical Ophthalmology, Institute of Ophthalmology, London, United Kingdom. Supported in pan by the Welcome Trust ([AJlf] grant 04019/Z/94/Z/WRE/MB/ JAT), and by the Ulverscroft Foundation. Submitted for publication February 7, 1997; revised July 25, 1997; accepted July 28, 1997. Profmetary interest category: N. Reprint requests: Alison J. Hardcastle, Department of Molecular Genetics, Institute of Ophthalmology, University College London, 11-43 Bath Street, London, ECP/ 9EL, UK. 2750 Downloaded From: http://iovs.arvojournals.org/ on 05/03/2017 tional relationship between RP and CSNB has been highlighted in studies describing mutations in the same gene that result in an RP or a CSNB phenotype. Autosomal dominant CSNB and RP (adRP) are associated with mutations in the rhodopsin (RHO) gene on chromosome 3p,4'5 and mutations in the gene for the phosphodiesterase /?-subunit (PDEP) on chromosome 4p result in autosomal dominant CSNB (CSNB3)G or in autosomal recessive retinitis pigmentosa (arRP). 7 Genetic analyses of CSNBX families during the past decade have clearly established the heterogeneity of this disorder, implicating at least two genes on the proximal short arm of the X chromosome (Fig. 1). The first descriptions of genetic mapping for CSNBX suggested close linkage with the locus DXS7, and no evidence for genetic heterogeneity, 8 " 10 similar to the first reports of X-linked retinitis pigmentosa (XLRP). 1112 CSNBX displays phenotypic heterogeneity, with complete and incomplete forms defined by Investigative Ophthalmology & Visual Science, December 1997, Vol. 3, No. 13 Copyright © Association for Research in Vision and Ophthalmology Locus for CSNBX Between the RP2 and RP3 Loci the presence of slight rod function in the latter. Complete CSNBX (CSNB1) was mapped proximal to DXS7, and this locus was further refined by genetic analysis in families, without further clinical definition, to between the loci MAOA and DXS426 (Xpll.3 to Xpll.23). l8 ' M The map position of this disease indicates potential allelism with one form of XLRP (JilJ2).lr' Subsequently, a family clinically defined as incomplete CSNBX (CSNB2) was described with a key recombination placing the disease proximal to MAOB,n> consistent with the interval assignment for CSNB1 and also potentially allelic with RP2 (Fig. 1). Intrafamilial phenotypic heterogeneity became apparent when Pearce et al described patients with complete and incomplete forms of the disease within the same pedigree.17 The report of disease in a family with CSNB1 mapping proximal to TIMP-1 (Xpll.23) 18 suggested genetic heterogeneity, in that this genetically defined interval overlaps the previously defined CSNBX locus only by approximately 100 kb.19 More recently, evaluation of a single family places CSNBX between the markers OTC and DXS1003,20 a location that significantly overlaps the newly defined RP2 critical interval.Ir> Genetic heterogeneity was clearly established when the locus for CSNBX described in a clinically heterogeneous family placed the disease in Xp21.1.21 This interval is clearly distinct from other reported locations, bounded by the loci STR44 and DXS228, and is closely linked to the RP3 gene region, providing further evidence for a functional relationship between CSNBX and XLRP. ptcr — DXS1229 — DXS989 RP15 — DXS1048 ~~| Rl'6 _. —STK44 —DXSU10 — RPGR - * RP3 CSNBXa —OTC — I3XS1058 — I5XS556 __ —i 2751 In this study, we report a new location on proximal Xp for CSNBX (CSNB4), in a single large family, which is not associated with previously described XLRP loci. PATIENTS AND METHODS Clinical Assessment A diagnosis of CSNBX was based on detailed family history and comprehensive ophthalmic testing at Moorfields Eye Hospital, London, United Kingdom. Only men were affected. The phenotype was typical of the disorder with life-long symptoms of night blindness, reduction of central vision to between 6/12 and 6/36 and high degree of myopia. The electroretinogram (ERG) showed a negative potential without oscillatory potentials to bright white light and was small to dim blue light (Schubert-Bornschein-type ERG). Dark adaptation showed little evidence of a rod-cone break but spectral sensitivity testing demonstrated that rods mediated vision at short wavelength in the darkadapted state. Thus, the detectable rod function was such that the condition would be classified as incomplete. DNA Analysis All investigations followed the tenets of the Declaration of Helsinki, and informed consent and full institutional review board approval were obtained. The forward primer for each microsatellite was end-labeled with 32P-ydATP at 37°C for 45 minutes with T4 polynucleotide kinase (New England Biolabs, Hertfordshire, UK). Polymerase chain reaction (PCR) was performed as previously described.22 Alleles were detected by electrophoresing the PCR products on 6% denaturing polyacrylamide gels (Promega, Southhampton, UK). Details of primer sequences and PCR conditions for all microsatellites used in this study are available from Genome Database. COD1 — DXS993 — DXS1201 — I3XS228 Linkage Analysis _ _ CSNBXb Two-point linkage analysis for CSNBX and seven markers on proximal Xp was carried out with LINKAGE version 5.1 using MLINK (Columbia University, Primary Retinal New York, NY). The frequency of the CSNBX gene in Dysplas — DXS1003 CSNB2 AIED the general population was taken to be 0.0001. Penetrance values for carriers were set at 0.0000. Alleles at —TIMP1/I3XS426 _ — IDXS6616 _ marker loci were assumed to have equal frequency, 1 CSNB1 and alteration of frequencies did not affect significant — DXS225 1 results. ILINK was used to calculate 0 inax and Z,nax. 5 m Multipoint linkage analysis (LINKMAP) with loci orFIGURE l. Map of eye diseases on proximal Xp RP15* RP6, 1 1 21 b 20 13 1 der DXS556-DXS993-DXS1201 was performed, usKP3: CSNBX / COD1™ CSNBX , CSNBX/CNSB1, " distances of 1 cM and 2 cM, respecCSNB2,"' AIED™ Rl>2,i5 CSNB1,18 primary retinal dyspla- ing genetic tively.22'23 sia/7 Norrie disease,38 and exudative vitreoretinopathy.39 — DXS7 — MAOA/MAOB Nome 31sca.se "" — NDI' -4 and Ex udative Vitr< or ctinnpathy — DXS8080 -' CSNBX/CSNB1 — DXS8083 — Rl>2 Downloaded From: http://iovs.arvojournals.org/ on 05/03/2017 2752 Investigative Ophthalmology & Visual Science, December 1997, Vol. 38, No. 13 pter ,4 3 3 2 4 5 3 1 1 1 2 1 3 2 2 3 2 2 3 1 2 3 4 4 2 1 1 1 1 2 2 3 1 1 Y wr III-3 IV-4 IV-3 IV-5 3T1 V-5 V-6 <•) 2 . _ 3 • 1 . _ 2 3 • 4 • 2 1 1 1 ! . . • 2 • 3 ' 1 ' 1 ' —2 3 4 —3 ^•1 _ _ _ _ - -4 .3 1 .2 .1 3 1 1 3 1 1 4 43 1 • 2 q.3 5 2 3 1 n. "+2 2 VI-1 VI-2 FIGURE 2. Pedigree of CSNBX family showing haplotypes constructed with 17 microsatellites on proximal Xp, localizing disease to between markers DXS556 and DXS8080. Diseaseassociated haplotypes are shown as dark bars, and the hatched bar represents markers that were uninformative. One woman of unknown clinical status is included in the pedigree (?), and recombination events are highlighted (*). RESULTS Haplotype Analysis The family was analyzed with 17 polymorphic microsatellite marker loci on proximal Xp, spanning previously identified CSNBX and XLRP loci to create the haplotypes shown in Figure 2. Subject IV-2, an obligate carrier, is recombinant, relative to subjects IV-3, IV-4, and IV-5. This informative recombination locates the disease-associated haplotype proximal to DXS1110. The same crossover is observed in subject V-l, indicating that the recombination observed in IV-2 occurred in generation II of this branch of the family. The distal boundary of CSNBX in this family is further refined by a recombination event in subject V-7, an unaffected man who has inherited the diseaseassociated haplotype at DXS556, placing the disease proximal to this locus. Subject V-7 does not have night Downloaded From: http://iovs.arvojournals.org/ on 05/03/2017 blindness; his clinical status was reconfirmed recently at Moorfields. Subject V-3 is recombinant, relative to his carrier mother (IV-2), between the loci DXS8080 and DXS1201 (MAOB and DXS7 are uninformative), with the disease-associated haplotype located distal to DXS8080. The data shown indicate that V-5, a woman of unknown clinical status, is evidently a carrier of CSNBX. In summary, haplotype data clearly define a locus for CSNBX (CSNB4) between the loci DXS556 and DXS8080 on Xpll.4 to Xpll.3. Haplotypes also demonstrate that DXS1201 and DXS993 cosegregate with disease. Linkage Analysis Table 1 describes two-point lod scores between CSNB4 and key marker loci on proximal Xp. The informative Locus for CSNBX Between the RP2 and RP3 Loci TABLE 2753 l. Two-Point Linkage Analysis Between CSNB4 and Informative Xp Marker Loci LOD Score at Recombination Fraction of Locus 0.00 DXS1242 DXS1110 DXS556 DXS993 DXS1201 DXS8080 DXS1003 — 00 — 00 — 00 2.51 1.25 — 00 — 00 0.01 0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4 -2.06 0.36 0.93 2.47 1.25 -0.54 -0.46 -0.67 0.91 1.46 2.29 1.21 0.08 0.21 -0.12 1.02 1.54 2.06 1.14 0.28 0.43 0.14 1.00 1.49 1.81 1.05 0.35 0.50 0.28 0.92 1.37 1.56 0.95 0.36 0.49 0.35 0.80 1.21 1.31 0.82 0.34 0.44 0.36 0.66 1.02 1.04 0.68 0.30 0.37 0.32 0.50 0.80 0.77 0.53 0.25 0.28 0.25 0.33 0.56 0.51 0.37 0.18 0.18 loci chosen represent regions around CSNBXRP3 (DXS1242,DXS1110), CSNBX-/?P2 (DXS8080, DXS1003) and loci in the interval between these regions (DXS556,DXS993,DXS1201). The locus DXS1003, which lies within the RP2-CSNBX interval on Xpll.23 1 5 is not linked to CSNB4 (Z, mx = 0.50; ©max = 0.17). Instead, a significant lod score was obtained with DXS993 (Z»nilx = 2.51; 0 m a x = 0). DXS1110 showed considerably weaker linkage to CSNB4 (Z,,,^ = 1.03; 6 m a x = 0.11). Multipoint analysis was performed to determine the most likely location of CSNB4 in relation to DXS556, DXS993, and DXS1201. A maximum lod of 3.2 was scored for the locus order DXS556-1 c M (CSM34-DXS993)-2 cM-DXS1201. A one-lod confidence interval based on these data places the CSNB4 locus in the 24-cM interval proximal to DXS556. DISCUSSION CSNBX is know to be phenotypically and genetically heterogeneous, with three locations for the disease on proximal Xp. The most commonly reported locus seems to lie between MAOA and DXS426,13'14 overlapping other locations,16'20 and is consistent with the newly defined locus assignment for RP2.15 Bech-Hansen et al described another location proximal to TIMP-1,18 and a third locus for CSNBX linked to the RP3 gene region was reported by Bergen et al. 2i Aland Islands eye disease (AIED), a clinically variant form of CSNBX, has a genetic interval defined by the loci DXS7 and DXS255,24'25'26 which is compatible with the most commonly reported locus assignment for CSNBX. Haplotype analysis in this study using 17 microsatellites on proximal Xp has revealed a new location for CSNBX (CSNB4) between the loci DXS556 and DXS8080. The genetic interval is estimated to be 5 to 6 cM,22'23 and is not associated with localizations for 7 '•'max 0.36 1.03 1.54 2.51 1.25 0.36 0.50 0mnv 0.29 0.11 0.96 0.00 0.00 0.19 0.17 DXS1110, suggests the order DMD-DYSl-(DXS1110CSNBX-XLRP3)-DXS7-DXS1003, which is indicative of potential allelism with RP3. Another group has since reported a mutation in the RP3 gene {RPGR) causing CSNBX, confirming allelism.29 In contrast, multipoint linkage analysis in this study suggests the order DXS5561 cM-(CS7VB4-DXS993)-2 cM-DXS1201 with a maximum lod score of 3.2. These data, coupled with informative recombinations in the family described here, clearly distinguishes this disease from RP3, RP2, and their associated CSNBX loci. CSNB4 appears to map to the same interval as Xlinked cone-rod dystrophy (CODI).3031 COD/was subsequently refined to an interval bounded by the loci DXS1058 and DXS1201 in X p l l . 4 to Xpll.3, 3 2 with DXS993 showing no crossovers. It should also be noted that DXS993 cosegregates fully without recombination with CSNB4, therefore raising the possibility that CODI and CSNB4 could be allelic variants. Because mutations in Peripherin-RDS can cause c o n e rod dystrophy or RP, and as already discussed, mutations in RHO, PDEfi, and RPGR can cause CSNB and RP, it seems reasonable to assume that further studies of families with XLRP may reveal a potentially allelic locus with this newly defined 5- to 6-cM interval. It is particularly interesting to observe that many families with XLRP appear to segregate with the RP3 locus (that is, disease is distal to DXS7 and proximal to other XLRP loci), which is reportedly more common than RP2.3S However, relatively few mutations in the RPGR gene have been discovered to date. 2734 Because it is possible that another gene more proximal to RPGR is causing disease in these families, the potential for this new common interval for various forms of retinal dystrophy (CSNB4 and CODI) also segregating with an as yet undefined XLRP locus can not be excluded. RP327 or RP2.15 Key Words The genetic interval for CSNBX described by Bergen et al,21 combined with new data from a different family28 that show no recombination with the locus allelic, haplotype analysis, heterogeneity, stationary night blindness, X-linked congenital, X-linked retinitis pigmen tosa Downloaded From: http://iovs.arvojournals.org/ on 05/03/2017 2754 Investigative Ophthalmology & Visual Science, December 1997, Vol. 38, No. 13 Acknowledgments The authors thank the Human Genome Mapping Project (HGMP) Resource Centre for oligonucleotide provision and Dr. Arthur Bergen, Dr. Chris Inglehearn, and Neil Ebenezer for their advice during preparation of this manuscript. 15. References 16. 1. Kato M, Aonuma H, Kawamura H, Miura Y, Watanabe I. Possible pathogenesis of congenital stationary night blindness. JpnJ Ophthalmol. 1987; 31:88-101. 2. Sharp D, Arden GB, Kemp CR, Hogg CR, Bird AC. 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Genetic and physical mapping of five novel microsatellite markers on Xp21.l-pll.22. Genomics. 1995;25:279-281. Dib C, Faure S, Fizames C, et al. A comprehensive genetic map of the human genome based on 5,264 microsatellites. Nature. 1996;380:152-154. Schwartzn M, Rosenberg T. Aland Island eye disease: Linkage data. Genomics. 1991; 10:327-332. Alitalo T, Kruse TA, Forsius H, Eriksson AW, de la Chapelle A. Localization of the Aland Island eye disease locus to the pericentric region of the human X chromosome by linkage analysis. Am J Hum Genet. 1991;48:31-38. Glass LA, Good P, Coleman MP, et al. Genetic mapping of a cone and rod dysfunction (AIED) to the proximal short arm of the human X chromosome. / Med Genet. 1993; 30:1044-1050. Meindl A, Dry K, Herrmann K, et al. A gene (RPGR) with homology to the RCCI guanine nucleotide exchange factor is mutated in X-linked retinitis pigmentosa (RP3). Nat Genet. 1996; 13:35-42. Bergen AAB, ten Brink JB, Riemslag F, et al. 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Meindl A, W Berger, T Meitinger, et al. Norrie disease is caused by mutations in an extracellular protein resembling G-terminal globular domain of mucins. Nat Genet. 1993;2:139-143. 39. Chen ZY, Battinelli EM, Fielder A, et al. A mutation in the Norrie disease gene (NDP) associated with Xlinked familial exudative vitreoretinopathy. Nat Genet. 1993;5:180-183.