Genetics in medicine : official journal of the American College of Medical Genetics · 2025
Substitutions of nucleotides at the 3' ends of COL6A1/2/3 exons induce exon skipping associated with collagen VI-related muscular dystrophies and therapeutic strategies.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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Lee Seung-Ah, Ogawa Megumu, Saito Yoshihiko, Shimazaki Rui, Awaya Tomonari, Hosokawa Motoyasu, Kurosawa Ryo, Ohara Hiroaki, Takeuchi Akihide, Hayashi Shinichiro, Goto Yu-Ichi, Hagiwara Masatoshi, Nishino Ichizo, Noguchi Satoru
Аннотация
PURPOSE: Collagen VI-related muscular dystrophies, characterized by proximal muscle weakness and joint contractures, are caused by pathogenic variants in the genes, COL6A1 to COL6A3. A monoallelic variant at the last nucleotide of a COL6A1 exon was initially classified as a missense variant but acted as a splicing variant, resulting in exon skipping. Here, we evaluated whether single-nucleotide variants at the 3'-ends of COL6A1 to COL6A3 exons cause aberrant splicing.
METHODS: Ten relevant variants were identified in patients from our repository or public databases, and their muscle COL6A1 to COL6A3 transcripts were analyzed. The effects of the variants on splicing were also analyzed by minigene assay and SpliceAI in silico prediction.
RESULTS: Transcripts from muscles of individuals with suspected collagen VI-related phenotypes showed exon skipping (skipping rate >12%). Findings of minigene assay and in silico prediction experiments supported these findings. Two therapeutic approaches, splicing correction of pre-messenger RNA or gene silencing of mature messenger RNA were assessed. Among them, gene silencing using short interfering RNAs targeting the skipped transcripts proved to be effective in restoring collagen VI in cells containing the pathogenic variant.
CONCLUSION: Single-nucleotide variants at the 3'-ends of exons can lead to aberrant splicing, and allele-specific gene silencing targeting such variants is a promising therapeutic strategy.
METHODS: Ten relevant variants were identified in patients from our repository or public databases, and their muscle COL6A1 to COL6A3 transcripts were analyzed. The effects of the variants on splicing were also analyzed by minigene assay and SpliceAI in silico prediction.
RESULTS: Transcripts from muscles of individuals with suspected collagen VI-related phenotypes showed exon skipping (skipping rate >12%). Findings of minigene assay and in silico prediction experiments supported these findings. Two therapeutic approaches, splicing correction of pre-messenger RNA or gene silencing of mature messenger RNA were assessed. Among them, gene silencing using short interfering RNAs targeting the skipped transcripts proved to be effective in restoring collagen VI in cells containing the pathogenic variant.
CONCLUSION: Single-nucleotide variants at the 3'-ends of exons can lead to aberrant splicing, and allele-specific gene silencing targeting such variants is a promising therapeutic strategy.