A growing list of insulin gene mutations causing a new form of monogenic diabetes has drawn increasing attention over the past seven years. The mutations have been identified in the untranslated regions of the insulin gene as well as the coding sequence of preproinsulin including within the signal peptide, insulin B-chain, C-peptide, insulin A-chain, and the proteolytic cleavage sites both for signal peptidase and the prohormone convertases. These mutations affect a variety of different steps of insulin biosynthesis in pancreatic beta cells. Importantly, although many of these mutations cause proinsulin misfolding with early onset autosomal dominant diabetes, some of the mutant alleles appear to engage different cellular and molecular mechanisms that underlie beta cell failure and diabetes. In this article, we review the most recent advances in the field and discuss challenges as well as potential strategies to prevent/delay the development and progression of autosomal dominant diabetes caused by INS-gene mutations. It is worth noting that although diabetes caused by INS gene mutations is rare, increasing evidence suggests that defects in the pathway of insulin biosynthesis may also be involved in the progression of more common types of diabetes. Collectively, the (pre)proinsulin mutants provide insightful molecular models to better understand the pathogenesis of all forms of diabetes in which preproinsulin processing defects, proinsulin misfolding, and ER stress are involved. (C) 2014 Elsevier Ltd. All rights reserved.

Liu, M., Sun, J., Cui, J., Chen, W., Guo, H., Barbetti, F., et al. (2015). INS-gene mutations: from genetics and beta cell biology and clinical disease. MOLECULAR ASPECTS OF MEDICINE, 42, 3-18 [10.1016/j.mam.2014.12.001].

INS-gene mutations: from genetics and beta cell biology and clinical disease

BARBETTI, FABRIZIO;
2015

Abstract

A growing list of insulin gene mutations causing a new form of monogenic diabetes has drawn increasing attention over the past seven years. The mutations have been identified in the untranslated regions of the insulin gene as well as the coding sequence of preproinsulin including within the signal peptide, insulin B-chain, C-peptide, insulin A-chain, and the proteolytic cleavage sites both for signal peptidase and the prohormone convertases. These mutations affect a variety of different steps of insulin biosynthesis in pancreatic beta cells. Importantly, although many of these mutations cause proinsulin misfolding with early onset autosomal dominant diabetes, some of the mutant alleles appear to engage different cellular and molecular mechanisms that underlie beta cell failure and diabetes. In this article, we review the most recent advances in the field and discuss challenges as well as potential strategies to prevent/delay the development and progression of autosomal dominant diabetes caused by INS-gene mutations. It is worth noting that although diabetes caused by INS gene mutations is rare, increasing evidence suggests that defects in the pathway of insulin biosynthesis may also be involved in the progression of more common types of diabetes. Collectively, the (pre)proinsulin mutants provide insightful molecular models to better understand the pathogenesis of all forms of diabetes in which preproinsulin processing defects, proinsulin misfolding, and ER stress are involved. (C) 2014 Elsevier Ltd. All rights reserved.
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/13 - Endocrinologia
English
Con Impact Factor ISI
Liu, M., Sun, J., Cui, J., Chen, W., Guo, H., Barbetti, F., et al. (2015). INS-gene mutations: from genetics and beta cell biology and clinical disease. MOLECULAR ASPECTS OF MEDICINE, 42, 3-18 [10.1016/j.mam.2014.12.001].
Liu, M; Sun, J; Cui, J; Chen, W; Guo, H; Barbetti, F; Arvan, P
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2108/173012
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