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Minigene splicing assessment of 20 novel synonymous and intronic glucokinase gene variants identified in patients with maturity‐onset diabetes of the young
Author(s) -
Tiulpakov Anatoly,
Zubkova Natalia,
Makretskaya Nina,
Krasnova Tatiana S.,
Melnikova Anna I.,
Fedyaeva Alena S.,
Vasilyev Evgeny,
Petrov Vasily M.,
Rubtsov Petr M.
Publication year - 2020
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.23919
Subject(s) - minigene , biology , rna splicing , in silico , glucokinase , exon , genetics , gene , alternative splicing , maturity onset diabetes of the young , computational biology , mutation , rna
The next‐generation sequencing (NGS) has become a routine method for diagnostics of inherited disorders. However, assessment of the discovered variants may be challenging, especially when they are not predicted to change the protein sequence. Here we performed a functional analysis of 20 novel or rare intronic and synonymous glucokinase ( GCK ) gene variants identified by targeted NGS in 1,130 patients with maturity‐onset diabetes of the young. Human Splicing Finder, ver 3.1 and a precomputed index of splicing variants (SPIDEX) were used for in silico prediction. In vitro effects of GCK gene variants on splicing were tested using a minigene expression approach. In vitro effect on splicing was shown for 9 of 20 variants, including two synonymous substitutions. In silico and in vitro results matched in about 50% of cases. The results demonstrate that novel or rare apparently benign GCK gene variants should be regarded as potential splicing mutations.