Transcriptional and translational effects of intronic CAPN3 gene mutations.

Human Mutation
A C NascimbeniC Angelini

Abstract

Variants of unknown significance in the CAPN3 gene constitute a significant challenge for genetic counselling. Despite the frequency of intronic nucleotide changes in this gene (15-25% of all mutations), so far their pathogenicity has only been inferred by in-silico analysis, and occasionally, proven by RNA analysis. In this study, 5 different intronic variants (one novel) that bioinformatic tools predicted would affect RNA splicing, underwent comprehensive studies which were designed to prove they are disease-causing. Muscle mRNA from 15 calpainopathy patients was analyzed by RT-PCR and splicing-specific-PCR tests. We established the previously unrecognized pathogenicity of these mutations, which caused aberrant splicing, most frequently by the activation of cryptic splicing sites or, occasionally, by exon skipping. The absence or severe reduction of protein demonstrated their deleterious effect at translational level. We concluded that bioinformatic tools are valuable to suggest the potential effects of intronic variants; however, the experimental demonstration of the pathogenicity is not always easy to do even when using RNA analysis (low abundance, degradation mechanisms), and it might not be successful unless splicing-spec...Continue Reading

Citations

Mar 27, 2012·BMC Musculoskeletal Disorders·Simon HauerslevThomas O Krag
Aug 10, 2011·Current Opinion in Neurology·Vincenzo NigroGiulio Piluso
Dec 4, 2015·Yonsei Medical Journal·Hyung Jun ParkYoung Chul Choi
Apr 29, 2020·Neuropathology and Applied Neurobiology·M CerinoS Attarian
Aug 25, 2015·Journal of Clinical Neuromuscular Disease·Jose D Avila, David Lacomis
Sep 27, 2019·Journal of Neurology·Andrea BarpRobert Y Carlier
Oct 16, 2019·Annals of Clinical and Translational Neurology·Fabiola MavillardMacarena Cabrera-Serrano
Jan 3, 2021·Journal of Neuromuscular Diseases·L Ten DamAnneke J van der Kooi

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Datasets Mentioned

BETA
AF209502.1

Methods Mentioned

BETA
biopsies
PCR
biopsy
electrophoresis

Software Mentioned

NetGene2

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