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. 2021 Jan 18;11(1):57.
doi: 10.3390/jpm11010057.

The Mutation Spectrum of Maturity Onset Diabetes of the Young (MODY)-Associated Genes among Western Siberia Patients

Dinara E Ivanoshchuk  1   2 , Elena V Shakhtshneider  1   2 , Oksana D Rymar  2 , Alla K Ovsyannikova  2 , Svetlana V Mikhailova  1 , Veniamin S Fishman  1 , Emil S Valeev  1 , Pavel S Orlov  1   2 , Mikhail I Voevoda  1
Affiliations

The Mutation Spectrum of Maturity Onset Diabetes of the Young (MODY)-Associated Genes among Western Siberia Patients

Dinara E Ivanoshchuk et al. J Pers Med. .

Abstract

Maturity onset diabetes of the young (MODY) is a congenital form of diabetes characterized by onset at a young age and a primary defect in pancreatic-β-cell function. Currently, 14 subtypes of MODY are known, and each is associated with mutations in a specific gene: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, KCNJ11, ABCC8, and APPL1. The most common subtypes of MODY are associated with mutations in the genes GCK, HNF1A, HNF4A, and HNF1B. Among them, up to 70% of cases are caused by mutations in GCK and HNF1A. Here, an analysis of 14 MODY genes was performed in 178 patients with a MODY phenotype in Western Siberia. Multiplex ligation-dependent probe amplification analysis of DNA samples from 50 randomly selected patients without detectable mutations did not reveal large rearrangements in the MODY genes. In 38 patients (37% males) among the 178 subjects, mutations were identified in HNF4A, GCK, HNF1A, and ABCC8. We identified novel potentially causative mutations p.Lys142*, Leu146Val, Ala173Glnfs*30, Val181Asp, Gly261Ala, IVS7 c.864 -1G>T, Cys371*, and Glu443Lys in GCK and Ser6Arg, IVS 2 c.526 +1 G>T, IVS3 c.713 +2 T>A, and Arg238Lys in HNF1A.

Keywords: GCK; HNF1A; HNF1B; HNF4A; MODY; diabetes mellitus; maturity onset diabetes of the young; multiplex ligation-dependent probe amplification; next-generation sequencing; population; single-nucleotide variant.

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Conflict of interest statement

The authors declare that they have no conflicts of interest related to the publication of this article.

Figures

Figure 1
Figure 1
The study design. DNA: deoxyribonucleic acid, MLPA: multiplex ligation-dependent probe amplification, MODY: maturity onset diabetes of the young, SNV: single-nucleotide variant, WES: whole-exome sequencing.
Figure 2
Figure 2
Screened MODY families (A–L) with novel identified variants in genes GCK and HNF1A. A grey filled symbol: a patient with prediabetes, MT: altered allele, SB: stillbirth, WT: wild type allele, ?/?: persons not genotyped, ?: a person with unknown health status. * RefSeq reference transcript: GCK (NM_000162.5), ABCC8 (NM_000352.3), HNF1B (NM_000458.2), and HNF1A (NM_000545.6).
Figure 2
Figure 2
Screened MODY families (A–L) with novel identified variants in genes GCK and HNF1A. A grey filled symbol: a patient with prediabetes, MT: altered allele, SB: stillbirth, WT: wild type allele, ?/?: persons not genotyped, ?: a person with unknown health status. * RefSeq reference transcript: GCK (NM_000162.5), ABCC8 (NM_000352.3), HNF1B (NM_000458.2), and HNF1A (NM_000545.6).
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