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Vol 48(2014) N 2 p. 248-253; DOI 10.1134/S0026893314020071 Full Text

E.L. Igudin1,2, P.V. Spirin1, V.S. Prassolov1,2, N.A. Zubkova3, E.E. Petryaikina4, A.N. Tyul'pakov3, P.M. Rubtsov1,2*

Functional Characterization of Two Novel Splicing Mutations of Glucokinase Gene Associated with Maturity-Onset Diabetes of the Young Type 2 (MODY2)

1Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, 119991, Russia
2Moscow Physico-Technical Institute, Dolgoprudnyi, Moscow Region, 141700, Russia
3Endocrinology Research Center, Moscow, 117036, Russia
4Morozov Children's Hospital, Moscow, 119049, Russia

*rubtsov@eimb.ru
Received - 2013-09-20; Accepted - 2013-10-16

Two novel mutations in the glucokinase gene (GCK) have been identified in patients with maturityonset diabetes of the young type-2 (MODY2), i.e., a C-for-G substitution at position -1 of the acceptor splice site of intron 7 (c. 864-1G>C) and a synonymous c.666C>G substitution (GTC>GTG, p.V222V) at exon 6. An analysis of the splicing products obtained upon the transfection of human embryonic HEK293 cells with GCK minigene constructs carrying these mutations showed that both substitutions impaired normal splicing. As a result of c.864-1G>C, the usage of the normal acceptor site was blocked, which activated cryptic acceptor splice sites within intron 7 and generated several aberrant RNAs containing fragments of intron 7. The synonymous substitution c.666C>G created a novel donor splice site in exon 6, which results in the formation of an abnormal GCK mRNA with a 16-nucleotide deletion in exon 6. In vitro experiments on minigene splicing confirmed the inactivating effect of these mutations on glucokinase gene expression.

MODY2 diabetes, glucokinase gene, splicing mutation, minigene expression, cryptic splicing sites, aberrant splicing products, nonsense-mediated mRNA decay



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