5′ splice site GC>GT and GT>GC variants differ markedly in terms of their functionality and pathogenicity |
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Authors: | Jin‐Huan Lin,Emmanuelle Masson,Arnaud Boulling,Matthew Hayden,David N. Cooper,Claude F rec,Zhuan Liao,Jian‐Min Chen |
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Affiliation: | Jin‐Huan Lin,Emmanuelle Masson,Arnaud Boulling,Matthew Hayden,David N. Cooper,Claude Férec,Zhuan Liao,Jian‐Min Chen |
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Abstract: | In the human genome, most 5′ splice sites (~99%) employ the canonical GT dinucleotide whereas a small minority (~1%) use the noncanonical GC dinucleotide. The functionality and pathogenicity of 5′ splice site GT>GC (+2T>C) variants have been extensively studied but we know very little about 5′ splice site GC>GT (+2C>T) variants. Herein, we have addressed this deficiency by performing a meta‐analysis of reported +2C>T “pathogenic” variants together with a functional analysis of engineered +2C>T substitutions using a cell culture‐based full‐length gene splicing assay. Our results establish proof of concept that +2C>T variants are qualitatively different from +2T>C variants in terms of their functionality and suggest that, in sharp contrast to +2T>C variants, most if not all +2C>T variants have no pathological relevance. Our findings have important implications for interpreting the clinical relevance of +2C>T variants and understanding the evolutionary switching between GT and GC 5′ splice sites in mammalian genomes. |
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Keywords: | +2C>T variant +2T>C variant 5′ splice site full‐length gene splicing assay Human Gene Mutation Database noncanonical GC dinucleotide |
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