Identification of Ala2Thr mutation in insulin gene from a Chinese MODY10 family.

Abstract

More than 80% of maturity-onset diabetes of the young (MODY) in Chinese is genetically unexplained. To investigate whether the insulin gene (INS) mutation is responsible for some Chinese MODY, we screened INS mutations causing MODY10 in MODY pedigrees and explored the potential pathogenic mechanisms. INS mutations were screened in 56 MODY familial probands. Structure-function characterization and clinical profiling of identified INS mutations were conducted. An INS mutation, at the position 2 alanine-to-threonine substitution (A2T), was identified and co-segregated with hyperglycemia in a MODY pedigree. The A2T mutation converted an α-helix into a β-sheet at the N-terminal of the signal peptide (SP) of preproinsulin. The A2T mutation did not affect preproinsulin translocation across endoplasmic reticulum (ER) membrane, but impaired its SP cleavage within the ER. In INS-1 cells transfected with an A2T mutant, glucose-stimulated insulin secretion (GSIS) was significantly decreased, while BiP luciferase activities were significantly increased compared to that of wild type (WT). We identified an INS-A2T mutation cosegregating with diabetes in a Chinese MODY pedigree. This mutation severely impaired SP cleavage and thus blocked the formation of proinsulin, resulting in enhanced ER stress, which may be responsible for decreased insulin secretion and subsequently, the onset of MODY10.

• Authors: Juan Zhang, Yanjun Liu, Ming Li, Xiaoxu Ge, Ying Wang, Xin Huang, Di Yang, Rong Zhang, Yating Chen, Ming Lu, Jun Yin, Mingqiang Song, Yongfeng Wang, Yanzhong Wang, Feng Wang, Meisheng Jiang, Limei Liu
• Journal: Molecular and cellular biochemistry (Mol Cell Biochem) Vol. 470 Issue 1-2 Pg. 77-86 (Jul 2020) ISSN: 1573-4919 [Electronic] Netherlands
• PMID: 32405973 (Publication Type: Journal Article)

Chemical References

• Insulin
• Threonine
• Glucose
• Alanine

Topics

• Adult
• Alanine (genetics)
• Cell Line
• China
• Diabetes Mellitus, Type 2 (genetics)
• Endoplasmic Reticulum Stress
• Family Health
• Female
• Genetic Predisposition to Disease
• Glucose (metabolism)
• Humans
• Hyperglycemia (genetics)
• Insulin (chemistry, genetics)
• Male
• Middle Aged
• Mutation
• Mutation, Missense
• Pedigree
• Protein Structure, Secondary
• Structure-Activity Relationship
• Threonine (genetics)
• Young Adult