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Review Article Eye Disorders: Primary Hereditary Diseases of the Retina

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Review Article Eye Disorders: Primary Hereditary Diseases of the Retina JMed Genet 1994;31:903-915 903 Review article J Med Genet: first published as 10.1136/jmg.31.12.903 on 1 December 1994. Downloaded from Recent advances in the gene map of inherited eye disorders: primary hereditary diseases of the retina, choroid, and vitreous Philip J Rosenfeld, Victor A McKusick, Joanna S Amberger, Thaddeus P Dryja The diagnosis and basic understanding ofmany rance, but the mutations are actually recessive genetic ocular disorders have been aided by the at the cellular level since tumours arise only if identification of the disease causing chromo- both copies of the retinoblastoma gene are somal loci. These chromosomal loci have inactivated in a sensitive cell. These tumour been mapped using the candidate gene or the inducing null mutations can arise by intragenic positional cloning approaches. This review will deletion, insertion, or translocation, by single focus on genetic disorders that primarily affect nucleotide changes that affect coding or spli- ocular function with emphasis on the most cing sequences, or by epigenetic abnormalities recent advances in the chromosomal mapping such as hypermethylation of the promoter re- of these disorders. In particular, we will con- gion.3-'3 Some retinoblastoma families show centrate on the genetic diseases affecting the evidence of reduced or incomplete penetrance. posterior segment of the eye including the ret- The molecular basis of reduced penetrance has ina, choroid, and vitreous. The success of link- been investigated in eight different families.""'7 age analysis has relied heavily on previous Two families with reduced penetrance have clinical classifications and there are numerous mutations in the promoter region of the re- reports of distinct ocular diseases mapping to tinoblastoma gene that decrease but do not specific chromosomal loci. However, there are eliminate the Rb gene product and three fam- also many examples in which a well defined ilies have a mutation that produces a mutant disease maps to any of a number of chro- protein with presumed diminished tumour sup- mosomal loci. This genetic phenomenon is pressor activity. One of the families studied http://jmg.bmj.com/ known as non-allelic or locus heterogeneity actually has "pseudo-low penetrance" owing to and can be viewed as reflecting the eye's limited independently derived Rb mutations in distant repertoire of responses to a variety of genetic relatives. 7 In another two families, no common lesions. Another emerging pattern is that of intragenic haplotypes were identified in rel- "gene sharing" in which different mutations atives with retinoblastoma and no mutations within the same gene can cause clinically dis- were identified in the Rb genes.'6 These two tinct ocular diseases. Mapping of mendelian families could be other examples of "pseudo- on September 25, 2021 by guest. Protected copyright. genetic disorders has helped refine the clinical low penetrance" with relatives having in- classifications and has led to examples of both dependently derived Rb mutations. Howe Laboratory, "lumping" and "splitting". Departnent of Ophthalmology, Colour blindness Harvard Medical Ocular School, Massachusetts tumours PROTAN AND DEUTAN SERIES Eye and Ear RETINOBLASTOMA The red and green visual pigment genes have Infirmary, 243 Charles Retinoblastoma, an embryonic neoplasm ofthe been cloned, sequenced, and mapped.'820 Street, Boston, retina, is the most common primary Massachusetts 02114, intraocular Mutations in these genes are the molecular USA malignancy in infants and children. The av- basis for X linked colour vision abnor- P J Rosenfeld erage annual incidence ofretinoblastoma in the malities.2'-23 Genes for the red and green T P Drya US population younger than 10 years old is opsins lie on the long arm ofthe X chromosome Center for Medical 10-9 per million.' The gene maps to chro- within Xq28. These genes are arranged in a Genetics, The Johns mosome 13q14, consists of 27 exons spanning tandem array with one copy of the red pigment Hopkins University 180 to 388 bp of genomic DNA, produces a gene at School of Medicine, the 5' end and from one to five green Blalock Building, 4-7 kb transcript, and encodes a nuclear phos- pigment genes located downstream in a head Room 1007, 600 N phoprotein consisting of 928 amino acids. to tail configuration presumably arising from Wolfe Street, The complete gene sequence is available.2 The unequal homologous recombination Baltimore, Maryland, events. 21287-4922, USA retinoblastoma (Rb) gene is a model for a class Only a single green pigment gene is expressed V A McKusick ofrecessive cancer genes where wild type alleles from this locus, probably the most proximal J S Amberger have a tumour suppressor function. Retino- copy.24 More than 95% of cases of red-green Correspondence to blastoma predisposition segregates as an colour blindness arise from mutant genotypes Dr Rosenfeld. autosomal dominant trait with 90% penet- owing to unequal intra- and intergenic re- 904 Rosenfeld, McKusick, Amberger, Dryja combination events giving rise to deletions or pathological studies of eyes from patients show hybrid genes within the tandem array of pig- abnormal or absent cones.43 There is evidence ment genes.2' 25-28 These mutations are the gen- that the genetic locus for rod monochromacy J Med Genet: first published as 10.1136/jmg.31.12.903 on 1 December 1994. Downloaded from etic basis for protanopia (absence of red colour is on chromosome 14. In this report, a 20 vision), protanomaly (anomalous red colour year old white woman with rod monochromacy vision), deuteranopia (absence of green colour was found to have a 14; 14 Robertsonian trans- vision), and deuteranomaly (anomalous green location and shown to be isodisomic for the colour vision). A missense mutation within the maternal chromosome 14. The responsible human green visual pigment gene is another locus on chromosome 14 has not been iden- cause of deuteranomaly.29 There is a direct tified. correlation between anomalous red/green vis- ion as detected by psychophysical experiments and the shifts in the in vitro absorption maxima Congenital stationary night blindness of hybrid pigments produced from cloned Congenital stationary night blindness (CSNB) cDNAs when compared to normal cone pig- is a group of genetically heterogeneous retinal ments.30-32 In normal trichromats who display disorders characterised by non-progressive person to person variability in red colour night blindness. The disease can be inherited matching, two common alleles of the red pig- as an autosomal dominant, autosomal re- ment gene have been identified and the re- cessive, or X linked trait, and there can be spective shifts in their absorption maxima can phenotypic heterogeneity even between fam- account for the differences in psychophysical ilies with the same inheritance pattern. Elec- testing.32-34 In general, persons with ab- troretinographic evidence indicates an intact normalities in red-green discrimination have cone system but the rod system can be variably no other signs of retinal disease. affected. The complete type has no detectable The complete loss of red and green cone rod function, while the incomplete type has function results in blue cone monochromacy, reduced rod function. Reduced visual acuity also known as incomplete achromotopsia. and nystagmus are variable clinical features of Males with this X linked trait use blue cones this disease. Myopia is often associated with X exclusively under photopic conditions and gen- linked and recessive forms. A dominant form erally have an acuity of only around 20/200. of CSNB can be caused by certain missense These persons are capable of limited hue mutations in the rhodopsin gene.45-4' These discrimination but only at intermediate light mutations are distinct from those responsible levels.3536 Blue cone monochromats have re- for retinitis pigmentosa, a progressive de- arrangements within the red and green visual generation ofboth rods and cones. Dryja et al'6 pigment gene cluster that result in the func- could not find a rhodopsin mutation in a subject tional loss of both classes of opsin genes.3738 with the Nougaret type of CSNB, perhaps the These mutations fall into two classes. In one most thoroughly studied form of autosomal class, the loss of functional genes is mediated dominant CSNB. A type of CSNB usually by unequal homologous recombination and associated with myopia, nystagmus, and de- point mutations. A second class involves the creased visual acuity has been designated http://jmg.bmj.com/ deletion of a locus control region upstream of CSNB 1 and mapped to the short arm of the the red and green pigment gene cluster. The X chromosome at position Xp 11 .3.4851 The affected upstream region can normally function frequent occurrence of myopia in this disorder as an activator of cone specific gene expression is believed to be a pleiotropic effect of the in transgenic mice.39 unidentified CSNB gene rather than the result of a closely linked second gene.5' The gene for CSNB 1 might be allelic with unidentified genes on September 25, 2021 by guest. Protected copyright. TRITANOPIA responsible for retinitis pigmentosa and ocular Tritanopia, the absence of blue colour vision, albinism which have been assigned to the same differs from the other colour vision disorders region by linkage studies.52-56 because it is inherited as an autosomal dom- inant trait with variable penetrance. The gene encoding the cone blue sensitive pigment has Ocular albinism been cloned, sequenced, and mapped to chro- Nettleship-Falls type ocular albinism or ocular mosome 7 at position 7q31.3-q32.'82'41 Point albinism type 1 (OA1) is inherited as an X mutations within the blue pigment gene have linked recessive disorder. The fundamental ab- been associated with tritanopia.4 142 normality is believed to be defective mel- anogenesis within all pigment-containing cells, but the pigmentation appears grossly abnormal ROD MONOCHROMACY only in the eye. Affected males present with The absence of functional cones is known as decreased visual acuity, nystagmus, and head total achromatopsia or rod monochromacy.
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