A novel nonsense mutation in CEP290 induces exon skipping and leads to a relatively mild retinal phenotype.
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Publication year
2010Source
Investigative Ophthalmology and Visual Science, 51, 7, (2010), pp. 3646-52ISSN
Annotation
01 juli 2010
Publication type
Article / Letter to editor
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Organization
Human Genetics
Ophthalmology
Journal title
Investigative Ophthalmology and Visual Science
Volume
vol. 51
Issue
iss. 7
Page start
p. 3646
Page end
p. 52
Subject
IGMD 3: Genomic disorders and inherited multi-system disorders; NCEBP 2: Evaluation of complex medical interventions; NCMLS 6: Genetics and epigenetic pathways of diseaseAbstract
PURPOSE. To identify the genetic defect in a family with variable retinal phenotypes. The proband had a diagnosis of Leber congenital amaurosis (LCA), whereas her two cousins had an early-onset severe retinal dystrophy (EOSRD) with useful vision. A distant family member had retinitis pigmentosa (RP). METHODS. DNA samples of the affected family members were genotyped with 250 K genome-wide SNP microarrays. Genetic defects were localized by linkage analysis and homozygosity mapping, and candidate genes were analyzed by sequencing. Patients underwent a full ophthalmic examination. RESULTS. Compound heterozygous mutations in CEP290 were identified in the proband and her two cousins: the frequent c.2991+1655A>G founder mutation and a novel nonsense mutation in exon 7 (c.451C>T, p.Arg151X). The proband had nystagmus, hyperopia, a flat electroretinogram (ERG), and decreased visual acuity (20/250) from birth. The two cousins had minimal scotopic ERG responses at the age of 2. In one of these patients, visual acuity had reached a level of 20/32 at age 5, which is high for patients with CEP290 mutations. Analysis of the CEP290 mRNA in affected individuals revealed altered splice forms in which either exon 7 or exons 7 and 8 were skipped. In both mutant cDNA products, the open reading frame was not disrupted. Furthermore, homozygosity mapping and mutation analysis in the distant family member affected by RP revealed a homozygous mutation in MERTK, but no CEP290 mutations. This MERTK mutation was heterozygously present in the most severely affected (LCA) patient, but was absent in the two more mildly affected cousins. CONCLUSIONS. A novel nonsense mutation in CEP290 results in nonsense-associated altered splicing. That the remaining open reading frame is intact may explain the less severe phenotype observed in the two affected cousins. The additional heterozygous mutation in MERTK may clarify the more severe phenotype in the proband. This study extends the phenotypic spectrum of CEP290-associated diseases at the mild end.
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- Academic publications [238441]
- Electronic publications [122537]
- Faculty of Medical Sciences [90373]
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