Dataset Information

Alport syndrome caused by a COL4A5 deletion and exonization of an adjacent AluY.

ABSTRACT: Mutation-induced activation of splice sites in intronic repetitive sequences has contributed significantly to the evolution of exon-intron structure and genetic disease. Such events have been associated with mutations within transposable elements, most frequently in mutation hot-spots of Alus. Here, we report a case of Alu exonization resulting from a 367-nt genomic COL4A5 deletion that did not encompass any recognizable transposed element, leading to the Alport syndrome. The deletion brought to proximity the 5' splice site of COL4A5 exon 33 and a cryptic 3' splice site in an antisense AluY copy in intron 32. The fusion exon was depleted of purines and purine-rich splicing enhancers, but had low levels of intramolecular secondary structure, was flanked by short introns and had strong 5' and Alu-derived 3' splice sites, apparently compensating poor composition and context of the new exon. This case demonstrates that Alu splice sites can be activated by outlying deletions, highlighting Alu versatility in shaping the exon-intron organization and expanding the spectrum of mutational mechanisms that introduce repetitive sequences in mRNAs.

SUBMITTER: Nozu K

PROVIDER: S-EPMC4190880 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Alport syndrome caused by a COL4A5 deletion and exonization of an adjacent AluY.

Nozu Kandai K Iijima Kazumoto K Ohtsuka Yasufumi Y Fu Xue Jun XJ Kaito Hiroshi H Nakanishi Koichi K Vorechovsky Igor I

Molecular genetics & genomic medicine 20140528 5

Mutation-induced activation of splice sites in intronic repetitive sequences has contributed significantly to the evolution of exon-intron structure and genetic disease. Such events have been associated with mutations within transposable elements, most frequently in mutation hot-spots of Alus. Here, we report a case of Alu exonization resulting from a 367-nt genomic COL4A5 deletion that did not encompass any recognizable transposed element, leading to the Alport syndrome. The deletion brought to ...[more]

PMID: 25333070

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Project description:Background and objectivesX-linked Alport syndrome is caused by mutations in the COL4A5 gene. Although many COL4A5 mutations have been detected, the mutation detection rate has been unsatisfactory. Some men with X-linked Alport syndrome show a relatively mild phenotype, but molecular basis investigations have rarely been conducted to clarify the underlying mechanism.Design, setting, participants, & measurementsIn total, 152 patients with X-linked Alport syndrome who were suspected of having Alport syndrome through clinical and pathologic investigations and referred to the hospital for mutational analysis between January of 2006 and January of 2013 were genetically diagnosed. Among those patients, 22 patients had suspected splice site mutations. Transcripts are routinely examined when suspected splice site mutations for abnormal transcripts are detected; 11 of them showed expected exon skipping, but others showed aberrant splicing patterns. The mutation detection strategy had two steps: (1) genomic DNA analysis using PCR and direct sequencing and (2) mRNA analysis using RT-PCR to detect RNA processing abnormalities.ResultsSix splicing consensus site mutations resulting in aberrant splicing patterns, one exonic mutation leading to exon skipping, and four deep intronic mutations producing cryptic splice site activation were identified. Interestingly, one case produced a cryptic splice site with a single nucleotide substitution in the deep intron that led to intronic exonization containing a stop codon; however, the patient showed a clearly milder phenotype for X-linked Alport syndrome in men with a truncating mutation. mRNA extracted from the kidney showed both normal and abnormal transcripts, with the normal transcript resulting in the milder phenotype. This novel mechanism leads to mild clinical characteristics.ConclusionsThis report highlights the importance of analyzing transcripts to enhance the mutation detection rate and provides insight into genotype-phenotype correlations. This approach can clarify the cause of atypically mild phenotypes in X-linked Alport syndrome.

Dataset Information

Alport syndrome caused by a COL4A5 deletion and exonization of an adjacent AluY.

Publications

Alport syndrome caused by a COL4A5 deletion and exonization of an adjacent AluY.

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