Identification of heterozygous mutations of ABCC8 gene responsible for maturity-onset diabetes of the young with exome sequencing.

Background: Although the MODY12 subtype, caused by ABCC8 mutations, is rare, it is highly sensitive to sulfonylureas. The identification of ABCC8 mutations in patients clinically diagnosed with MODY has the ability to contribute to the precise management of diabetes.

Methods: Genetic analysis of two families with MODY were conducted using whole-exome sequencing (WES) and Sanger sequencing. The spatial structures of the mutant proteins were constructed using MODELLER and PyMOL software to provide further evidence of pathogenicity.

Results: The heterozygous missense mutations V357I and R1393H in ABCC8 were found in probands of two unrelated MODY pedigrees, which co-segregated with the hyperglycemic phenotypes in these two pedigrees. Detection of the V357I mutation enabled the proband of family A to successfully transfer from insulin to sulfonylurea (SU). After 3 months of follow-up for the SU trial, the HbA1c level of proband A improved from 12.4% at the initial diagnosis to 7.20%. Proband B was treated with insulin because of pregnancy and poor islet function. In silico analysis indicated that the R1393H mutation resulted in a longer hydrogen bond distance to L1389 and cleavage of carbon-hydrogen bonds to V1395, A1390, and L1389.

Conclusions: We have described two pathogenic missense mutations in ABCC8 in Chinese families with MODY. Our findings support the heterogeneity in the clinical features of MODY12 caused by ABCC8 mutations.