De novo mutations in the CRX homeobox gene associated with Leber congenital amaurosis

Freund, Carol L.; Wang, Q.-L.; Chen, Shiming; Muskat, Barbara; Wiles, C. D.; Sheffield, Val C.; Jacobson, Samuel G.; McInnes, Roderick R.; Zack, Donald J.; Stone, Edwin M.

doi:10.1038/ng0498-311

Cited by 262 publications

(134 citation statements)

References 14 publications

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“…Indeed, six LCA genes have been hitherto mapped namely, LCA1 and LCA4 on chromosome 17p13.1, 10,16,17 LCA2 on chromosome 1p31, 5 LCA3 on chromosome 14q24, 11 LCA5 on chromosome 6q11-q16 12 and LCA6 on chromosome 19q13.3. 7 Among them, four out of six have been identified: the retinal specific guanylate cyclase gene (retGC1, LCA1, 4 ), the gene encoding the 65-kD protein specific to the retinal pigment epithelium (RPE65, LCA2, 5 ), the cone-rod homeo box-containing gene (CRX, LCA6, 7 ) and the gene encoding the arylhydrocarbon receptor interacting protein-like 1, only 2 Mb centromeric from LCA1 (LCA4, 10 ). LCA3 and LCA5 respectively account for the disease in a consanguineous Saudi Arabian LCA family and a multigenerational kindred of Old Order River Brethren, a religious isolate descended from Swiss immigrants to America in the 1750s.…”

Section: Discussionmentioning

confidence: 99%

Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis

et al. 2001

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Section: Discussionmentioning

confidence: 99%

Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis

et al. 2001

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“…The following genes are known to be associated with LCA: GUCY2D, RPE65, SPATA7, AIPL1, LCA5, RPGRIP1, CRX, CRB1, CEP290, IMPDH1, RD3, RDH12, KCNJ13, LRAT and TULP1. [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] It is difficult to estimate the proportion of patients with mutations in the different genes, as some, such as IMPDH1 (LCA11) is considered to be rare, other, as CEP290 accounts for almost 20%, and for some such as TULP1 and LRAT the number is uncertain. One of the most studied LCA genes is CRB1 at 1q31q32.1, which consists of 12 exons and encodes a protein Crumbs homologue that participates in determination and maintenance of photoreceptor architecture.…”

Section: Introductionmentioning

confidence: 99%

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

et al. 2013

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This study aimed to identify genetic mechanisms underlying severe retinal degeneration in one large family from northern Sweden, members of which presented with early-onset autosomal recessive retinitis pigmentosa and juvenile macular dystrophy. The clinical records of affected family members were analysed retrospectively and ophthalmological and electrophysiological examinations were performed in selected cases. Mutation screening was initially performed with microarrays, interrogating known mutations in the genes associated with recessive retinitis pigmentosa, Leber congenital amaurosis and Stargardt disease. Searching for homozygous regions with putative causative disease genes was done by high-density SNP-array genotyping, followed by segregation analysis of the family members. Two distinct phenotypes of retinal dystrophy, Leber congenital amaurosis and Stargardt disease were present in the family. In the family, four patients with Leber congenital amaurosis were homozygous for a novel c.2557C4T (p.Q853X) mutation in the CRB1 gene, while of two cases with Stargardt disease, one was homozygous for c.5461-10T4C in the ABCA4 gene and another was carrier of the same mutation and a novel ABCA4 mutation c.4773 þ 3A4G. Sequence analysis of the entire ABCA4 gene in patients with Stargardt disease revealed complex alleles with additional sequence variants, which were evaluated by bioinformatics tools. In conclusion, presence of different genetic mechanisms resulting in variable phenotype within the family is not rare and can challenge molecular geneticists, ophthalmologists and genetic counsellors.

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“…[11][12][13] Taken together, these three genes account for only 27% of LCA cases in our series. 14 The search for genotype-phenotype correlations allowed us to demonstrate that retGC1 gene mutations are responsible for a congenital cone-rod dystrophy with dramatic and invariable cone dysfunction, while RPE65 gene mutations are responsible for a severe yet progressive rod-cone dystrophy, still different from the congenital stationary blindness caused by retGC1 gene mutations.…”

Section: Introductionmentioning

confidence: 99%

Spectrum of retGC1 mutations in Leber's congenital amaurosis

et al. 2000

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Leber's congenital amaurosis (LCA) is the earliest and most severe form of all inherited retinal dystrophies responsible for congenital blindness. Genetic heterogeneity of LCA has been suspected since the report by Waardenburg of normal children born to affected parents. In 1995 we localised the first disease causing gene, LCA1, to chromosome 17p13 and confirmed the genetic heterogeneity. In 1996 we ascribed LCA1 to mutations in the photoreceptor-specific guanylate cyclase gene (retGC1). Here, we report on the screening of the whole coding sequence of the retGC1 gene in 118 patients affected with LCA. We found 22 different mutations in 24 unrelated families originating from various countries of the world. It is worth noting that all retGC1 mutations consistently caused congenital cone-rod dystrophy in our series, confirming the previous genotype-phenotype correlations we were able to establish. RetGC1 is an essential protein implicated in the phototransduction cascade, especially in the recovery of the dark state after the excitation process of photoreceptor cells by light stimulation. We postulate that the retGC1 mutations hinder the restoration of the basal level of cGMP of cone and rod photoreceptor cells, leading to a situation equivalent to consistent light exposure during photoreceptor development, explaining the severity of the visual disorder at birth.

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De novo mutations in the CRX homeobox gene associated with Leber congenital amaurosis

Cited by 262 publications

References 14 publications

Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis

Complete exon-intron structure of the RPGR-interacting protein (RPGRIP1) gene allows the identification of mutations underlying Leber congenital amaurosis

Novel mutations in CRB1 and ABCA4 genes cause Leber congenital amaurosis and Stargardt disease in a Swedish family

Spectrum of retGC1 mutations in Leber's congenital amaurosis

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