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Genetic Heterogeneity Among Blue-Cone Monochromats Jeremy Nathans,* Irene H

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Genetic Heterogeneity Among Blue-Cone Monochromats Jeremy Nathans,* Irene H Am.J. Hum. Genet. 53:987-100(, 1993 Genetic Heterogeneity among Blue-Cone Monochromats Jeremy Nathans,* Irene H. Maumenee,t Eberhart Zrenner,1 Bettina Sadowski,1 Lindsay T. Sharpe,5 Richard A. Lewis,'1 Egill Hansen,# Thomas Rosenberg,** Marianne Schwartztt John R. Heckenlively,:4 Elias Traboulsi,t Roger Klingaman,§§ N. Torben Bech-Hansen,1111 G. Robert LaRoche,## Roberta A. Pagon,*** William H. Murphey,ttt and Richard G. Weleberttt Howard Hughes Medical Institute, Departments of Molecular Biology and Genetics, Neuroscience, and tWilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore; $University Eye Hospital, Tubingen; §Neurologische Universititsklinik, Freiburg im Breisgau, Germany; I1Cullen Eye Institute, Baylor College of Medicine, Houston; #Department of Ophthalmology, The National Hospital, University of Oslo, Oslo; **National Eye Clinic, Hellerup, Denmark; ttDepartment of Pediatrics, University Hospital, Copenhagen; 44Jules Stein Eye Insititute, UCLA School of Medicine, Los Angeles; "Southern College of Optometry, Memphis; 1t1Alberta Children's Hospital, Calgary; ##IWK Hospital for Children, Halifax, Nova Scotia; ***Departments of Pediatrics and Ophthalmology, University of Washington School of Medicine, Seattle; and ttDepartment of Ophthalmology, The Oregon Health Sciences University, Portland Summary Thirty-three unrelated subjects with blue-cone monochromacy or closely related variants of blue-cone monochromacy were examined for rearrangements in the tandem array of genes encoding the red- and green- cone pigments. In 24 subjects, eight genotypes were found that would be predicted to eliminate the function of all of the genes within the array. As observed in an earlier study, the rearrangements involve either deletion of a locus control region adjacent to the gene array or loss of function via homologous recombination and point mutation. One inactivating mutation, Cys203-to-Arg, was found in 15 probands who carry single genes and in both visual pigment genes in one subject whose array has two genes. This mutation was also found in at least one of the visual pigment genes in 1 subject whose array has multiple genes and in 2 of 321 control subjects, suggesting that preexisting Cys203-to-Arg mutations constitute a reservoir of chromosomes that are predisposed to generate blue-cone-monochromat genotypes by unequal homologous recombination and/or gene conversion. Two other point mutations were identified: (a) Arg247-to-Ter in one subject with a single red-pigment gene and (b) Pro3`-to-Leu in one subject with a single 5' red-3' green hybrid gene. The observed heterogeneity of genotypes points to the existence of multiple one- and two-step mutational pathways to blue-cone monochromacy. Introduction or a shift in the spectral sensitivity of one of the cone visual pigments (anomalous trichromacy). Dichromacy Normal human color vision involves a comparison of and anomalous trichromacy affecting the red and green the relative extents of excitation of three classes of cones arise from rearrangements in the genes encoding cone photoreceptors. The most common forms of in- the red- and green-sensitive cone pigments, located on herited color-vision deficiency involve an alteration in the long arm of the X chromosome (Nathans et al. one of the three cone systems (Boynton 1979). These 1986a; Deeb et al. 1992). These highly homologous alterations cause a loss of cone function (dichromacy) genes reside in a head-to-tail tandem array, an arrange- ment that predisposes them to unequal intra- and inter- genic homologous recombination (Nathans et al. Received May 3, 1993; final revision received July 1, 1993. 1986b; Vollrath et al. 1988; Feil et al. 1990). Greater Address for correspondence and reprints: J. Nathans, PCTB 805, than 95% of color-vision variation in the red- and Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205. green-cone systems arises from gene rearrangements of C 1993 by The American Society of Human Genetics. All rights reserved. this type. 0002-9297/93/5305-0002$02.00 Blue-cone monochromacy is a rare X-linked condi- 987 988 Nathans et al. tion characterized by an absence of red- and green-cone Subjects, Material, and Methods function (Blackwell and Blackwell 1961; Alpern 1974; Pokorny et al. 1979). Under photopic conditions, vi- Human Subjects sion is mediated exclusively by blue cones (Hess et al. The diagnosis of blue-cone monochromacy was 1989). Under these conditions, the blue-cone mono- based on either a history of severe congenital color- chromat experiences a colorless world: without a com- blindness and a pedigree consistent with an X-linked parison between different photoreceptor classes the vi- mode of inheritance (fig. 1) or, in the absence of a con- sual system cannot resolve the independent variables of clusive pattern of inheritance, psychophysical data in- wavelength composition and light intensity. It is inter- dicating the presence of blue-cone function and the esting that, at intermediate light levels, blue-cone mono- absence of red- and green-cone function. Most subjects chromats show a weak interaction between rod and also have reduced acuity, some degree of photophobia, blue-cone signals which permits crude hue discrimina- and a history of nystagmus in childhood. In those sub- tion (Reitner et al. 1991). Blue-cone monochromacy is jects who have undergone more extensive psychophysi- typically associated with low acuity, in the range 0.3- cal testing, photopic threshold measurements indicate 0.1, which is exacerbated in some individuals by a pro- an absence of red- and green-cone function and the gressive degeneration of the central retina, the region presence of blue-cone function. For some subjects, most enriched in cone photoreceptors (Fleischman and clinical and psychophysical data have been published O'Donnell 1981; Nathans et al. 1989). elsewhere, as follows: in the family of HS123, subjects 1 In earlier work we identified eight different rear- and 2 correspond to 111-1 and IV-1, respectively, in Pa- rangements in the red- and green-pigment gene array in gon et al. (1987); in the family of HS129, subjects 1, 2, blue-cone monochromats from 12 families (Nathans et 3, and 4 correspond to 111-7, either 111-8 or 111-9, 111-22, al. 1989). The rearrangements were found to be of two and IV-18, respectively, in Fleischman and O'Donnell types. In one type, unequal homologous recombination (1981); HS1075 and HS1188 correspond to BTW and had reduced to one the number of visual pigment genes HH, respectively, in Hansen (1979); HS1066, HS1067, in the array. In three families with this type of rear- HS1068, HS1077, and HS1078 correspond to KS, MP, rangement, a point mutation was observed which PS, SB, and FB, respectively, in Hess et al. (1989) and disrupted a conserved disulfide bond by replacing Reitner et al. (1991); and the families of HS1580, Cys203 with Arg (C203R; amino acid substitutions are HS1581, and HS1582 correspond to families 41, 47, referred to by the identity of the wild-type residue, ab- and 79, respectively, in Andreasson and Tornquist breviated by using the single-letter amino acid designa- (1991). Control samples were obtained from male par- tion, followed by the codon number, followed by the ticipants in a study unrelated to vision and from cadets introduced residue). In the second type of rearrange- at the United States Air Force Academy. Proband ment, six different deletions ranging in size from 0.6 kb HS129 is African-American; all other probands are of to 55 kb were found in, or adjacent to, otherwise typi- European descent. The control subjects were sampled cal gene arrays. All of these deletions encompass a com- from the U.S. population and are predominantly Cau- mon region between 3.1 kb and 3.7 kb 5' of the array. casian. Recent experiments in which sequences 5' of the red- and green-pigment gene array direct expression of a DNA Collection and Analysis beta-galactosidase reporter gene in transgenic mice indi- Venous blood samples (5-20 cc) were obtained from cate that the region between 3.1 kb and 3.7 kb 5' of the each subject and were processed as described elsewhere array functions as an essential activator of cone-specific (Sung et al. 1991a). Southern blot analysis of the red- gene expression (Wang et al. 1992). and green-pigment gene array was performed with the The present paper describes a molecular genetic anal- following combinations of restriction digests and ysis of 33 new families with blue-cone monochromacy probes: to visualize fragment Z, HindIII digests were or closely related variants of blue-cone monochro- probed with an 800-bp BamHI-HindIII partial-digest macy. One of the goals of this study is to determine the fragment located between 8.0 kb and 8.8 kb 5' of the range and relative frequencies of genetic events respon- red-pigment gene transcription start site (Nathans et al. sible for this disorder. The molecular heterogeneity re- 1989); to visualize fragments Bg, Br5 Cg, and Cr (sub- ported here suggests that some of the clinical heteroge- scripts "g" and "r" refer to fragments derived from the neity among blue-cone monochromats may have a green- and red-pigment genes, respectively), EcoRI- genetic basis. BamHI double digests first were probed with a 300-bp HS056 HS1 10 HS113 HS116 HS1 19 HS1 23 1 2 3 4 1 2 I4 1 2 3 5 6 2 HS1 29 HS1 30 HS215 HS252 HS278 HS871 I HS1 026 HS1066 HS1067 HS1068 HS1075 I 2 I HS1077 HS1 120 HSI1S8 HS1419 990 HS1 556 HS1 580 HS1 581 onw (E] L1R 1 HS1 582 HS1 751 Ia HS1 770 HS1 773 ?or D 991 992 Nathans et al. HS1 784 HS1 835 HS1 840 2 Figure I Pedigrees of blue-cone monochromat families. Blackened symbols denote affected subjects; half-blackened symbols denote obligate carriers; hatched symbols denote variant color vision; "P" denotes "protan"; "D" denotes "deutan"; "LV" denotes "low visual acuity"; and a question mark (?) denotes uncertain diagnosis.
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