Biological behaviors of mutant proinsulin contribute to the phenotypic spectrum of diabetes associated with insulin gene mutations

MOLECULAR AND CELLULAR ENDOCRINOLOGY

卷:518

Article

Wang, Heting¹  Saint-Martin, Cecile²  Xu, Jialu¹  Ding, Li¹  Wang, Ruodan¹  Feng, Wenli¹  Liu, Ming^1,5  Shu, Hua¹  Fan, Zhenqian³  Haataja, Leena⁴  Arvan, Peter⁴  Bellanne-Chantelot, Christine²  Cui, Jingqiu¹  Huang, Yumeng¹ 

[1] Tianjin Med Univ Gen Hosp, Dept Endocrinol & Metab, 154 Anshan Rd, Tianjin 300052, Peoples R China

[2] Sorbonne Univ, Pitie Salpetriere Hosp, AP HP, Dept Genet, Paris, France

[3] Tianjin Med Univ, Hosp 2, Dept Endocrinol & Metab, Tianjin, Peoples R China

[4] Univ Michigan, Sch Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI USA

[5] Tianjin Inst Endocrinol, Tianjin, Peoples R China

关键词: Neonatal diabetes mellitus;    Maturity onset diabetes of the young;    Proinsulin misfolding;    ER stress;    Dominant negative effect;    Insulin gene mutations;   

DOI  :  10.1016/j.mce.2020.111025

来源: Elsevier

【 摘 要 】

Insulin gene mutation is the second most common cause of neonatal diabetes (NDM). It is also one of the genes involved in maturity-onset diabetes of the young (MODY). We aim to investigate molecular behaviors of different INS gene variants that may correlate with the clinical spectrum of diabetes phenotypes. In this study, we concentrated on two previously uncharacterized MODY-causing mutants, proinsulin-p.Gly44Arg [G(B20)R] and p.Pro52Leu [P(B28)L] (a novel mutant identified in one French family), and an NDM causing proinsulin-p. (Cys96Tyr) [C(A7)Y]. We find that these proinsulin mutants exhibit impaired oxidative folding in the endoplasmic reticulum (ER) with blocked ER export, ER stress, and apoptosis. Importantly, the proinsulin mutants formed abnormal intermolecular disulfide bonds that not only involved the mutant proinsulin, but also the coexpressed WT-proinsulin, forming misfolded disulfide-linked proinsulin complexes. This impaired the intracellular trafficking of WT-proinsulin and limited the production of bioactive mature insulin. Notably, although all three mutants presented with similar defects in folding, trafficking, and dominant negative behavior, the degrees of these defects appeared to be different. Specifically, compared to MODY mutants G(B20)R and P(B28)L that partially affected folding and trafficking of co-expressed WT-proinsulin, the NDM mutant C(A7)Y resulted in an almost complete blockade of the ER export of WT-proinsulin, decreasing insulin production, inducing more severe ER stress and apoptosis. We thus demonstrate that differences in cell biological behaviors among different proinsulin mutants correlate with the spectrum of diabetes phenotypes caused by the different INS gene mutations.

【 授权许可】

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