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Review
. 2015 Apr:42:3-18.
doi: 10.1016/j.mam.2014.12.001. Epub 2014 Dec 24.

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

Ming Liu  1 , Jinhong Sun  2 , Jinqiu Cui  3 , Wei Chen  2 , Huan Guo  2 , Fabrizio Barbetti  4 , Peter Arvan  5
Affiliations
Review

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

Ming Liu et al. Mol Aspects Med. 2015 Apr.

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.

Keywords: Diabetes; Endoplasmic reticulum stress; Insulin biosynthesis; Insulin gene mutation; Pancreatic beta cell; Proinsulin misfolding.

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Figures

Fig. 1
Fig. 1
The effects of INS-gene mutations on the major steps of insulin biosynthesis. INS-gene mutations have been identified in the untranslated regions of INS gene and the coding sequence encoding all functional domains of preproinsulin molecule, including signal peptide (SP, pink), insulin B-chain (blue), C-peptide (black), insulin A-chain (red), and the proteolytic cleavage sites of signal peptidase (SPase) as well as prohormone convertases (PC1/3 and PC2, green). The mutations affect all major steps of insulin biosynthesis. Twelve recessive mutations in the untranslated regions result in more than 80% decrease of insulin production due to either INS gene deletion or truncation, or failure of insulin translation initiation, or instability of insulin mRNA. SP mutations in the n-region (R6C/H) or h-region (L13R) cause defective translocation of preproinsulin into the ER. The mutation at SP cleavage site (A24D) impairs SP cleavage. The largest group of INS-gene mutations are the mutations that affect proinsulin folding in the endoplasmic reticulum (ER), impairing formation of three evolutionarily conserved native disulfide bonds, B7-A7, B19-A20, and A6-A11. H34D affects sorting efficiency of proinsulin into regulated secretory pathway. The non-cysteine mutations at the PC2 cleavage site (R89H/P/L) impairs processing of proinsulin. The mutations in the B-chain (F48S and F49L) and A-chain (V92L) affect insulin binding to the insulin receptor. All mutations that cause Mutant INS-gene-induced Diabetes of Youth (MIDY) are underlined.
Fig. 2
Fig. 2
Three functional regions of preproinsulin signal peptide and the mutations associated with diabetes. Preproinsulin signal peptide has three functional regions: n-region (green), h-region (red), and c-region (yellow). Diabetogenic INS-gene mutations have been found in all three regions. The mutations in the n-region (R6C/H) cause inefficient translcocation of preproinsulin across the ER membrane and lead to late-onset diabetes (LOD). The mutation in the h-region (L13R) causes mutant INS-gene-induced diabetes of young (MIDY). The cellular defect caused by L13R remains to be determined, but it is predicted to affect the targeting and translocation of the mutant preproinsulin. The mutation at the signal peptide cleavage site (A24D) impairs normal signal peptide cleavage and causes proinsulin misfolding in the ER, leading to MIDY.
Fig. 3
Fig. 3
Solution structures of insulin analogs. A. Ensemble of NMR-derived structures DKP-insulin wild-type (WT). The A- and B-chains are shown in light and dark gray, respectively. B. Solution structures of V92L-DKP-insulin. The side chain of the mutant residue leucine (Leu) at the 3rd residue of insulin A-chain is shown in red. C. Solution structures of F48S-DKP-insulin. The side chain of the mutant residue serine (Ser) at the 24th residue of insulin B-chain is shown in red. Whereas V92L is compatible with native-like structure in accord with results of X-ray crystallography, F48S destabilizes the C-terminal strand of the B-chain. This figure is modified from Liu et al. (2010a).
Fig. 4
Fig. 4
Two preproinsulin signal peptide mutations cause distinct cellular defects in beta cells. A. Processing of Myc-tagged preproinsulin R6C and A24D in INS1 cells were examined by western blotting using anti-Myc antibody While most of preproinsulin-A24D presents as uncleaved preproinsulin, preproinsulin-R6C produces two populations: proinsulin and unprocessed preproinsulin. C–D. INS1 cells expressing Myc-tagged preproinsulin-WT, R6C or A24D were fully permeabilized and immunoblotted with anti-Myc (green) and anti-PDI (red) antibodies. Nuclei were counterstained with DAPI. In most cells expressing Myc-tagged preproinsulin-WT (A), anti-myc immunoreactable molecules presented as punctate insulin granule-like pattern (arrowheads) that were distinct from PDI. Preproinsulin-A24D lost the granule pattern and largely overlapped with PDI (B). Preproinsulin-R6C produces two major intracellular pools: one did indeed concentrate in distal tips (arrowheads) while another accumulated in a juxtanuclear location (arrows), and neither pool overlapped with PDI (C). E–G. The parallel sets of INS1 cells were selectively permeabilized by 0.01% digitonin and immunoblotted with anti-Myc (green) and anti-GM130 (red) antibodies. Nuclei were counterstained with DAPI. Unlike B–D, anti-myc immunoreactable molecules were detected only in the cells expressing Myc-tagged R6C (G). Such molecules appeared to accumulate in a juxtanuclear region close to Golgi marker GM130. H. A parallel well of the cells of G were pre-treated with 5uM brefeldin A (BFA) before being partially permeabilized and immunoblotted as in G. This figure is modified from Guo et al. (2014).
Fig. 5
Fig. 5
A proposed model of beta cell failure and diabetes caused by the defects in the early events of insulin biosynthesis. The preproinsulin signal peptide mutations in the n-region, i.e. R6C/H, result in a translocation defect of newly synthesized preproinsulin across the ER membrane (1). A certain fraction of untranslocatd preproinsulin relocates and accumulates in the juxtanuclear compartment, activating cytosolic response, promoting beta cell death, and leading to beta cell failure. The preproinsulin mutation at the signal peptide cleavage site, i.e. A24D, impairs normal cleavage of the signal peptide (2). This results in misfolding of downstream proinsulin domain. Twenty-eight reported gene mutations, e.g. C(A7)Y, lead to proinsulin misfolding in the ER (3). Misfolded mutant proinsulins not only induce ER stress and beta cell death, but also block the ER export of co-expressed proinsulin-WT, resulting in decreased insulin production from proinsulin-WT, leading to MIDY. This figure is modified from Guo et al. (2014).
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