CEP290 Mutation Spectrum and Delineation of the Associated Phenotype in a Large German Cohort: A Monocentric Study

Feldhaus, Britta; Weisschuh, Nicole; Nasser, Fadi; Hollander, Anneke I. den; Cremers, Frans P.M.; Zrenner, Eberhart; Kohl, Susanne; Zobor, Ditta

doi:10.1016/j.ajo.2019.11.012

Cited by 30 publications

(37 citation statements)

References 33 publications

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“…As this brain disorder considered a hallmark for JSRDs diagnosis is not present in the patient 3–7, Joubert syndrome's oculo-renal form was not recognized. Both substitutions: the c.3811C>T and the frequent: c.4723A>T identified in our patient have been reported in patients with isolated LCA and other retinal dystrophies but also in patients showing retinal disorders with MTS [ 15 , 17 , 20 , 21 ]. The substitution c.4723A>T (p.Lys1575*) identified in the patient no.…”

Section: Discussionsupporting

confidence: 70%

“…Patients with two nonsense variants appear to have worse visual acuity than patients with one nonsense and one missense CEP290 variant [ 15 , 16 ]. In a cohort of German patients with CEP290 variants, it has been observed that homozygous patients for the c.2991+1655G>A variant presented a more severe phenotype than compound heterozygotes with this intronic variant [ 17 ]. In our study group, it was difficult to observe any genotype–phenotype correlations similar to those presented in a German patient group, as there were no homozygotes for the variant p.Cys998* in our group of patients.…”

Section: Discussionmentioning

confidence: 99%

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Novel gene variants in Polish patients with Leber congenital amaurosis (LCA)

Skorczyk-Werner

Niedziela

Stopa

et al. 2020

Orphanet J Rare Dis

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Background Leber congenital amaurosis (LCA) is a rare retinal disease that is the most frequent cause of congenital blindness in children and the most severe form of inherited retinal dystrophies. To date, 25 genes have been implicated in the pathogenesis of LCA. As gene therapy is becoming available, the identification of potential treatment candidates is crucial. The aim of the study was to report the molecular basis of Leber congenital amaurosis in 22 Polish families. Methods Single Nucleotide Polymorphism-microarray for LCA genes or Next Generation Sequencing diagnostic panel for LCA genes (or both tests) were performed to identify potentially pathogenic variants. Bidirectional Sanger sequencing was carried out for validation and segregation analysis of the variants identified within the families. Results The molecular background was established in 22 families. From a total of 24 identified variants, 23 were predicted to affect protein-coding or splicing, including 10 novel variants. The variants were identified in 7 genes: CEP290, GUCY2D, RPE65, NMNAT1, CRB1, RPGRIP1, and CRX. More than one-third of the patients, with clinical LCA diagnosis confirmed by the results of molecular analysis, appeared to be affected with a severe form of the disease: LCA10 caused by the CEP290 gene variants. Intronic mutation c.2991+1655A>G in the CEP290 gene was the most frequent variant identified in the studied group. Conclusions This study provides the first molecular genetic characteristics of patients with Leber congenital amaurosis from the previously unexplored Polish population. Our study expands the mutational spectrum as we report 10 novel variants identified in LCA genes. The fact that the most frequent causes of the disease in the studied group of Polish patients are mutations in one out of three genes that are currently the targets for gene therapy (CEP290, GUCY2D, and RPE65) strongly emphasizes the importance of the molecular background analyses of LCA in Polish patients.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

Novel gene variants in Polish patients with Leber congenital amaurosis (LCA)

Skorczyk-Werner

Niedziela

Stopa

et al. 2020

Orphanet J Rare Dis

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“…The unexpectedly mild phenotypes are due to the production of near-full-length proteins derived from non-canonical mRNA splicing that skips exons with truncating mutations. One of the interesting features of inherited retinal degenerations is the wide spectrum of phenotypic severity despite mutations in the same gene [20,[61][62][63][64][65][66][67]. Although some of these variations can be explained by disease-causing mutations per se (e.g.…”

Section: Discussionmentioning

confidence: 99%

Differential requirement of NPHP1 for compartmentalized protein localization during photoreceptor outer segment development and maintenance

Datta

Cribbs

Seo

2021

Preprint

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Nephrocystin (NPHP1) is a ciliary transition zone protein and its ablation causes nephronophthisis (NPHP) with partially penetrant retinal dystrophy. However, the precise requirements of NPHP1 in photoreceptors are not well understood. Here, we characterize retinal degeneration in a mouse model of NPHP1 and show that NPHP1 is required to prevent infiltration of inner segment plasma membrane proteins into the outer segment during the photoreceptor maturation. We demonstrate that Nphp1 gene-trap mutant mice, which were previously described as null, are in fact hypomorphs due to the production of a small quantity of functional mRNAs derived from nonsense-associated altered splicing and skipping of two exons including the one harboring the gene-trap. In homozygous mutant animals, inner segment plasma membrane proteins such as syntaxin-3 (STX3), synaptosomal-associated protein 25 (SNAP25), and interphotoreceptor matrix proteoglycan 2 (IMPG2) accumulate in the outer segment when outer segments are actively elongating. This phenotype, however, is spontaneously ameliorated after the outer segment elongation is completed. Retinal degeneration also occurs temporarily during the photoreceptor maturation but stops afterward. We further show that Nphp1 genetically interacts with Cep290, another NPHP gene, and that a reduction of Cep290 gene dose results in retinal degeneration that continues until adulthood in Nphp1 mutant mice. These findings demonstrate that NPHP1 is required for the confinement of inner segment plasma membrane proteins during the outer segment development, but its requirement diminishes as photoreceptors mature. Our study also suggests that additional mutations in other NPHP genes may influence the penetrance of retinopathy in human NPHP1 patients.

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“…Missense variants are rare. There is no clear genotype–phenotype correlation, and some studies showed contradictory results; patient homozygous for the most common intronic mutation had either better [ 6 ] or worse [ 7 ] final visual outcome. Perrault et al studied 47 subjects belonging to 40 families segregating CEP290 mutations and discovered that all patients displayed a severe cone-rod form of LCA with profound and early reduction in the visual function, along with high hyperopia and macular degeneration in the first decade of life [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

A Mild Phenotype Caused by Two Novel Compound Heterozygous Mutations in CEP290

Rafalska

Tracewska

Turno-Kręcicka

et al. 2020

Genes

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CEP290 is a ciliary gene frequently mutated in ciliopathies, resulting in a broad range of phenotypes, ranging from isolated inherited retinal disorders (IRDs) to severe or lethal syndromes with multisystemic involvement. Patients with non-syndromic CEP290-linked disease experience profound and early vision loss due to cone-rod dystrophy, as in Leber congenital amaurosis. In this case report, we describe two novel loss-of-function heterozygous alterations in the CEP290 gene, discovered in a patient suffering from retinitis pigmentosa using massive parallel sequencing of a molecular inversion probes library constructed for 108 genes involved in IRDs. A milder phenotype than expected was found in the individual, which serves to prove that some CEP290-associated disorders may display preserved cone function.

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CEP290 Mutation Spectrum and Delineation of the Associated Phenotype in a Large German Cohort: A Monocentric Study

Cited by 30 publications

References 33 publications

Novel gene variants in Polish patients with Leber congenital amaurosis (LCA)

Novel gene variants in Polish patients with Leber congenital amaurosis (LCA)

Differential requirement of NPHP1 for compartmentalized protein localization during photoreceptor outer segment development and maintenance

A Mild Phenotype Caused by Two Novel Compound Heterozygous Mutations in CEP290

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