Mutations in the CEP290 (NPHP6) Gene Are a Frequent Cause of Leber Congenital Amaurosis

Abstract

Leber congenital amaurosis (LCA) is one of the main causes of childhood blindness. To date, mutations in eight genes have been described, which together account for approximately 45% of LCA cases. We localized the genetic defect in a consanguineous LCA-affected family from Quebec and identified a splice defect in a gene encoding a centrosomal protein (CEP290). The defect is caused by an intronic mutation (c.2991+1655A-->G) that creates a strong splice-donor site and inserts a cryptic exon in the CEP290 messenger RNA. This mutation was detected in 16 (21%) of 76 unrelated patients with LCA, either homozygously or in combination with a second deleterious mutation on the other allele. CEP290 mutations therefore represent one of the most frequent causes of LCA identified so far.

Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

“…Moreover, several previous studies demonstrated that an affected gene from syndromic RP could also cause isolated retinal disease with no additional symptoms. Examples include CEP290, mutations in which can cause either JBS or Leber congenital amaurosis, 38 and CLN3, which is associated with Batten disease and nonsyndromic retinal degeneration. 39 The novel genotype-phenotype correlations described in this study enhance our knowledge of the molecular mechanisms of retinal dystrophies.…”

Mutations in LCA5 are an uncommon cause of Leber congenital amaurosis (LCA) type II

“…60%) [Perrault et al, 1999;Hanein et al, 2004]. Up to date, 13 LCA genes have been mapped, 10 of which have been identified: GUCY2D/retGC1 [Perrault et al, 1996], RPE65 [Marlhens et al, 1997], CRX [Swaroop et al, 1999], AIPL1 [Sohocki et al, 2000], RPGRIP1 [Dryja et al, 2001;Gerber et al, 2001], CRB1 [den Hollander et al, 2001;Gerber et al, 2002], LRAT [Thompson and Gal, 2003], TULP1 , RDH12 [Janecke et al, 2004;Perrault et al, 2004], CEP290 [den Hollander et al, 2006;Perrault et al, 2007]. Mutations in 3/10of them were shown to account for LCA type I (GUCY2D, RPGRIP1, CEP290) while, although less frequent, LCA type II was hitherto accounted for by mutations in 7/10 genes (RPE65, CRX, AIPL1, CRB1, LRAT TULP12, RDH12) [Perrault et al, 1999;Hanein et al, 2004;Perrault et al, 2004;Perrault et al, 2007].…”

“…Until the identification of mutations in the broadly expressed CEP290 gene in LCA [den Hollander et al, 2006;Perrault et al, 2007], disease-causing genes were characterized by a restricted pattern of expression in the photoreceptor cell layer or retinal pigment epithelium. The expression of CEP290 in ciliated cells gave additional support to the emerging role of ciliary dysfunction in isolated retinal dystrophies including LCA (RPGRIP1, MIM# 605446), retinitis pigmentosa (RPGR, MIM# 312610; RP1, MIM# 603937) and in syndromic retinal degenerations such as Bardet-Biedl syndrome (BBS, MIM# 209900), Senior-Loken syndrome (SNLS, MIM# 266900, MIM# 606995, MIM# 606996, MIM# 610189, MIM# 609254, MIM# 609237) and Joubert syndrome (JBTS, MIM# 608629, MIM# 609583, MIM# 610188, MIM# 610688).…”

Accumulation of the Raf-1 Kinase Inhibitory Protein (Rkip) Is Associated with Cep290-mediated Photoreceptor Degeneration in Ciliopathies

“…Cep290 mutations are associated with severe and syndromic disorders such as Joubert and Meckel-Gruber syndromes (35,36), as well as tissue restricted disease, such as Leber congenital amaurosis (37). Previously, we showed that in-frame deletion of 299 amino acids in Cep290 is associated primarily with retinal degeneration in the rd16 (retinal degeneration 16) mouse (32).…”