Insulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention
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Insulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention. / Meur, Gargi; Simon, Albane; Harun, Nasret; Virally, Marie; Dechaume, Aurélie; Bonnefond, Amélie; Fetita, Sabrina; Tarasov, Andrei I; Guillausseau, Pierre-Jean; Boesgaard, Trine Welløv; Pedersen, Oluf; Hansen, Torben; Polak, Michel; Gautier, Jean-François; Froguel, Philippe; Rutter, Guy A; Vaxillaire, Martine.
In: Diabetes, Vol. 59, No. 3, 2009, p. 653-61.Research output: Contribution to journal › Journal article › Research › peer-review
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T1 - Insulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention
AU - Meur, Gargi
AU - Simon, Albane
AU - Harun, Nasret
AU - Virally, Marie
AU - Dechaume, Aurélie
AU - Bonnefond, Amélie
AU - Fetita, Sabrina
AU - Tarasov, Andrei I
AU - Guillausseau, Pierre-Jean
AU - Boesgaard, Trine Welløv
AU - Pedersen, Oluf
AU - Hansen, Torben
AU - Polak, Michel
AU - Gautier, Jean-François
AU - Froguel, Philippe
AU - Rutter, Guy A
AU - Vaxillaire, Martine
PY - 2009
Y1 - 2009
N2 - OBJECTIVE: Heterozygous mutations in the human preproinsulin (INS) gene are a cause of nonsyndromic neonatal or early-infancy diabetes. Here, we sought to identify INS mutations associated with maturity-onset diabetes of the young (MODY) or nonautoimmune diabetes in mid-adult life, and to explore the molecular mechanisms involved. RESEARCH DESIGN AND METHODS: The INS gene was sequenced in 16 French probands with unexplained MODY, 95 patients with nonautoimmune early-onset diabetes (diagnosed at <35 years) and 292 normoglycemic control subjects of French origin. Three identified insulin mutants were generated by site-directed mutagenesis of cDNA encoding a preproinsulin-green fluorescent protein (GFP) (C-peptide) chimera. Intracellular targeting was assessed in clonal beta-cells by immunocytochemistry and proinsulin secretion, by radioimmunoassay. Spliced XBP1 and C/EBP homologous protein were quantitated by real-time PCR. RESULTS: A novel coding mutation, L30M, potentially affecting insulin multimerization, was identified in five diabetic individuals (diabetes onset 17-36 years) in a single family. L30M preproinsulin-GFP fluorescence largely associated with the endoplasmic reticulum (ER) in MIN6 beta-cells, and ER exit was inhibited by approximately 50%. Two additional mutants, R55C (at the B/C junction) and R6H (in the signal peptide), were normally targeted to secretory granules, but nonetheless caused substantial ER stress. CONCLUSIONS: We describe three INS mutations cosegregating with early-onset diabetes whose clinical presentation is compatible with MODY. These led to the production of (pre)proinsulin molecules with markedly different trafficking properties and effects on ER stress, demonstrating a range of molecular defects in the beta-cell.
AB - OBJECTIVE: Heterozygous mutations in the human preproinsulin (INS) gene are a cause of nonsyndromic neonatal or early-infancy diabetes. Here, we sought to identify INS mutations associated with maturity-onset diabetes of the young (MODY) or nonautoimmune diabetes in mid-adult life, and to explore the molecular mechanisms involved. RESEARCH DESIGN AND METHODS: The INS gene was sequenced in 16 French probands with unexplained MODY, 95 patients with nonautoimmune early-onset diabetes (diagnosed at <35 years) and 292 normoglycemic control subjects of French origin. Three identified insulin mutants were generated by site-directed mutagenesis of cDNA encoding a preproinsulin-green fluorescent protein (GFP) (C-peptide) chimera. Intracellular targeting was assessed in clonal beta-cells by immunocytochemistry and proinsulin secretion, by radioimmunoassay. Spliced XBP1 and C/EBP homologous protein were quantitated by real-time PCR. RESULTS: A novel coding mutation, L30M, potentially affecting insulin multimerization, was identified in five diabetic individuals (diabetes onset 17-36 years) in a single family. L30M preproinsulin-GFP fluorescence largely associated with the endoplasmic reticulum (ER) in MIN6 beta-cells, and ER exit was inhibited by approximately 50%. Two additional mutants, R55C (at the B/C junction) and R6H (in the signal peptide), were normally targeted to secretory granules, but nonetheless caused substantial ER stress. CONCLUSIONS: We describe three INS mutations cosegregating with early-onset diabetes whose clinical presentation is compatible with MODY. These led to the production of (pre)proinsulin molecules with markedly different trafficking properties and effects on ER stress, demonstrating a range of molecular defects in the beta-cell.
U2 - 10.2337/db09-1091
DO - 10.2337/db09-1091
M3 - Journal article
C2 - 20007936
VL - 59
SP - 653
EP - 661
JO - Diabetes
JF - Diabetes
SN - 0012-1797
IS - 3
ER -
ID: 18764931