<i>CRB1</i>
 mutations in inherited retinal dystrophies

Bujakowska, Kinga; Audo, Isabelle; Mohand‐Saïd, Saddek; Lancelot, Marie-Elise; Arnaiz‐Villena, Antonio; Germain, Aurore; Léveillard, Thierry; Letexier, Mélanie; Saraiva, Jean-Paul; Lonjou, Christine; Carpentier, Wassila; Sahel, José‐Alain; Bhattacharya, Siladitya; Zeitz, Christina

doi:10.1002/humu.21653

Cited by 158 publications

(219 citation statements)

References 57 publications

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“…Patients carrying CRB1 variants display an early-onset retinal degeneration with maculopathy and nummular pigmentations in the retina that are typical features for individuals with variants in CRB1. 17 As reported for other cases with RPGRIP1 variants, patient 81 had poor vision in the first year of life with nystagmus and hypermetropic eyes (+5.5/+6.0). 33 Early-onset visual impairment and nystagmus were also observed in patient 71 carrying GUCY2D variants who showed no ERG responses at the age of 1 year.…”

Section: Clinical Findingssupporting

confidence: 53%

“…[13][14][15] In addition, the AIPL1 variant p.(W278*) in exon 6, a conspicuous cluster of CRB1 variants in exons 7 and 9, and the GUCY2D exon 12 variant p.(R768W) together may explain~14% of the cases. 16,17 Therefore, prescreening of these 5 exons potentially identifies 26% of the mutations, serving as a cost-and time-effective genotyping procedure for LCA. Finally, screening of RPE65 and LRAT should uncover the cause of disease in 7 and 1% of LCA cases, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

et al. 2015

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Leber congenital amaurosis (LCA) represents the most severe form of inherited retinal dystrophies with an onset during the first year of life. Currently, 21 genes are known to be associated with LCA and recurrent mutations have been observed in AIPL1, CEP290, CRB1 and GUCY2D. In addition, sequence analysis of LRAT and RPE65 may be important in view of treatments that are emerging for patients carrying variants in these genes. Screening of the aforementioned variants and genes was performed in 64 Danish LCA probands. Upon the identification of heterozygous variants, Sanger sequencing was performed of the relevant genes to identify the second allele. In combination with prior arrayed primer extension analysis, this led to the identification of two variants in 42 of 86 cases (49%). Remarkably, biallelic RPE65 variants were identified in 16% of the cases, and one novel variant, p.(D110G), was found in seven RPE65 alleles. We also collected all previously published RPE65 variants, identified in 914 alleles of 539 patients with LCA or early-onset retinitis pigmentosa, and deposited them in the RPE65 Leiden Open Variation Database (LOVD). The in silico pathogenicity assessment of the missense and noncanonical splice site variants, as well as an analysis of their frequency in~60 000 control individuals, rendered 864 of the alleles to affect function or probably affect function. This comprehensive database can now be used to select patients eligible for gene augmentation or retinoid supplementation therapies.

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Section: Clinical Findingssupporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

et al. 2015

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“…Among 150 known CRB1 sequence variants, mutations in exon 7 are the most frequent (27%) and especially important for CRB1 function due to encoded laminin AG-like domain. 30,31 The c.5461-10T4C mutation was first reported by Maugeri et al, 32 although its function is still not resolved. The functional consequence of c.5461-10T4C was accessed in a study with the Exon Trapping System by Rivera et al, 33 who classified this nucleotide change as a rare sequence variant, as only correctly spliced exon was detected.…”

Section: Discussionmentioning

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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“…The severity of the CRB1/Crb1 phenotype is strongly dependent on the genetic background as different mutations cause various retinal phenotypes in human and mice (9,14,15). The lack of a clear genotype -phenotype correlation suggests that other Crumbs family members have a function influencing the severity of the retinal disease.…”

Section: Introductionmentioning

confidence: 99%

Targeted ablation of Crb2 in photoreceptor cells induces retinitis pigmentosa

Alves¹,

Pellissier²,

Vos³

et al. 2014

Human Molecular Genetics

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In humans, the Crumbs homolog-1 (CRB1) gene is mutated in autosomal recessive Leber congenital amaurosis and early-onset retinitis pigmentosa. In mammals, the Crumbs family is composed of: CRB1, CRB2, CRB3A and CRB3B. Recently, we showed that removal of mouse Crb2 from retinal progenitor cells, and consequent removal from Mü ller glial and photoreceptor cells, results in severe and progressive retinal degeneration with concomitant loss of retinal function that mimics retinitis pigmentosa due to mutations in the CRB1 gene. Here, we studied the effects of cell-type-specific loss of CRB2 from the developing mouse retina using targeted conditional deletion of Crb2 in photoreceptors or Mü ller cells. We analyzed the consequences of targeted loss of CRB2 in the adult mouse retina using adeno-associated viral vectors encoding Cre recombinase and short hairpin RNA against Crb2. In vivo retinal imaging by means of optical coherence tomography on retinas lacking CRB2 in photoreceptors showed progressive thinning of the photoreceptor layer and cellular mislocalization. Electroretinogram recordings under scotopic conditions showed severe attenuation of the a-wave, confirming the degeneration of photoreceptors. Retinas lacking CRB2 in developing photoreceptors showed early onset of abnormal lamination, whereas retinas lacking CRB2 in developing Mü ller cells showed late onset retinal disorganization. Our data suggest that in the developing retina, CRB2 has redundant functions in Mü ller glial cells, while CRB2 has essential functions in photoreceptors. Our data suggest that short-term loss of CRB2 in adult mouse photoreceptors, but not in Mü ller glial cells, causes sporadic loss of adhesion between photoreceptors and Mü ller cells.

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CRB1 mutations in inherited retinal dystrophies

Cited by 158 publications

References 57 publications

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

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

Targeted ablation of Crb2 in photoreceptor cells induces retinitis pigmentosa

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