Abstract
Deep intronic mutations are often ignored as possible causes of human disease. Using whole-exome sequencing, we analysed genomic DNAs of a Japanese family with two male siblings affected by ocular albinism and congenital nystagmus. Although mutations or copy number alterations of coding regions were not identified in candidate genes, the novel intronic mutation c.659-131 T > G within GPR143 intron 5 was identified as hemizygous in affected siblings and as heterozygous in the unaffected mother. This mutation was predicted to create a cryptic splice donor site within intron 5 and activate a cryptic acceptor site at 41nt upstream, causing the insertion into the coding sequence of an out-of-frame 41-bp pseudoexon with a premature stop codon in the aberrant transcript, which was confirmed by minigene experiments. This result expands the mutational spectrum of GPR143 and suggests the utility of next-generation sequencing integrated with in silico and experimental analyses for improving the molecular diagnosis of this disease.
Highlights
There is no obvious explanation for this low rate of detecting mutations
10% of mutations in disease-associated genes listed in the HGMD affect splicing, and most occur within or close to conserved consensus splice sites and are readily detected by Sanger sequencing of polymerase chain reaction (PCR) amplicons targeting coding exons
Deep intronic mutations associated with aberrant splicing of target genes are detected with increasing frequency in the genomes of patients with diseases, such as HPRT deficiency, Usher syndrome type 2, cystic fibrosis and megaloencephalic leukoencephalopathy with subcortical cysts type 121–24
Summary
The possibility that mutated genes other than GPR143 are responsible for OA1 seems unlikely, because linkage analysis of families without GPR143 mutations point to the OA1 locus (Xp22.3)[5,10,11,12,13,14] Another possibility is thatGPR143 mutations occur outside the coding region or include larger insertions or deletions. Mutations in coding regions nor copy number alterations of GPR143 or other candidate genes were not detected, detailed analysis of intronic sequences flanking target exons presented here show that ocular albinism in this family may be caused by the deep intronic mutation c.659-131. T > G in GPR143 (NM_000273.2) intron 5 that creates a cryptic donor splice site This mutation causes a 41-bp insertion in the transcript by creating a cryptic exon within intron 5
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