A Missense (c.T1424C:p.L475P) Mutation of ZYG11A Causes Maturity-Onset Diabetes of the Young

Abstract

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes inherited in an autosomal dominant mode. Approximately, 80% of Thai MODY families did not carry mutations of known MODY genes. This study aims, therefore, to identify an unknown causative gene of MODY in Thais. Exome sequencing was performed in DNA samples of two diabetic and one nondiabetic members of a MODY family with unknown genetic etiology. Only heterozygous non-synonymous variants with minor allele frequencies <0.01%, which were shared between the two diabetic but not existed in nondiabetic family members, were selected for segregation analysis. Among these, a missense mutation (NM_001004339, c.T1424C:p.L475P) in a gene encoding zyg-11 family member A (ZYG11A) showed complete segregation with diabetes in three generations. This mutation is not present in any database and not detected in nondiabetic controls (n = 400) as well as other MODY-X probands (n = 90). The amino acid residue L475 of ZYG11A is evolutionally conserved among many species. Several prediction software tools suggested a deleterious effect of the L475P mutation. ZYG11A acts as a target recruitment subunit of an E3 ubiquitin ligase complex, which plays an important role in degradation of cyclinB1- a regulatory protein involved in mitosis. Suppression of ZYG11A in 1.1B4 β-cell line by specific small interfering RNA (siRNA) significantly reduced cell proliferation (p = 0.001) while increased cyclinB1 protein levels (p = 0.001). Moreover, 1.1B4 cells overexpressing ZYG11A showed a significant increase in proliferation as compared to the control cells (p = 0.019) whereas this effect was not observed in the cells overexpressing the mutant ZYG11A (p = 0.659). Taken together, this finding demonstrates the crucial role of ZYG11A in β-cell cycle regulation. It also suggests heterozygous ZYG11A-L475P mutation as a cause of MODY in the Thai family studied. Disclosure C. Charoensuk: None. P. Jungtrakoon: None. W. Tangjittipokin: None. J. Sujjitjoon: None. N. Plengvidhya: None. P. Yenchitsomanus: None.