Objective::In contrast to the most commonly reported forms of maturity-onset diabetes of the young(MODY),including MODY2,MODY3 and MODY5,MODY6 is a relatively rare subtype.To investigate whether NEUROD1 is responsible for MODY in Chinese individuals,we screened its mutations in MODY pedigrees and explored the potential pathogenic mechanisms.Methods::Polymerase chain reaction direct sequencing was performed to screen NEUROD1 mutations in 32 Chinese MODY probands who were negative for the GCK/MODY2,HNF1A/MODY3 and HNF1B/MODY5 genes in this observational study.In addition,we enrolled 201 unrelated,non-diabetic control subjects of Han Chinese descent.The functional significance of newly identified mutations was analyzed using clinical phenotype,pathophysiology and three-dimensional structure studies.This study was approved by the Institutional Review Board of Shanghai Jiao Tong University Affiliated Sixth People’s Hospital,China(approval No.YS-2017-83)on March 3,2017.Results::E59Q(c.175 G>C,p.Glu59Gln),a heterozygous missense mutation in the NEUROD1 gene,was identified in one family with MODY.The Glu59 residue in NeuroD1 is highly conserved across mammalian species.Four diabetic patients carrying the mutation(a proband and her son,brother and sister)were lean,with a body mass index of 20.9(20.3-21.2)kg/m 2.Compared with their unaffected relatives(n=4),E59Q carriers(n=4)had significantly decreased ratios of fasting and 2-hour insulin to plasma glucose(both fasting plasma insulin/fasting plasma glucose and 2-hour postprandial plasma insulin/2-hour postprandial plasma glucose,P<0.005).The proband’s father had an E59Q mutation and normal glucose tolerance,which suggested non-penetrance.The E59Q mutation was not detected in other probands or in the 201 control subjects with normal glucose tolerance.Two salt-bridge bonds of Glu59 were disrupted at the Q59 mutation site.Conclusion::The NEUROD1-E59Q mutation changed the molecular conformation of the N-terminal in NeuroD1,which may decrease binding of the E59Q mutant to t
Juan ZhangYanyan JiangLi LiYanpeng WangMing LuYating ChenMingqiang SongXiaoxu GeMing LiYing WangFeng WangMiao YuMeisheng JiangYanjun LiuLimei Liu
