title: Frameshift mutations in the insulin gene leading to prolonged molecule of insulin in two families with Maturity-Onset Diabetes of the Young.
abstract: Mutations in the insulin (INS) gene rarely occur in patients with Maturity-Onset Diabetes of the Young (MODY). We aimed to describe in detail two MODY families with INS mutations. The INS gene was screened by direct sequencing. The probands and their affected relatives underwent a mixed-meal test. Mutation predictions were modeled using I-TASSER and were visualized by Swiss-PdbViewer. A novel heterozygous frameshift mutation p.Gln78fs in the INS gene was found in three generations of patients with clinically distinct diabetes. The single nucleotide deletion (c.233delA) is predicted to change and prolong amino acid sequence, resulting in aberrant proinsulin without native structures of C-peptide and A-chain. In the second family, the heterozygous mutation c.188-31G>A within the terminal intron was detected. The mother and her daughter were misdiagnosed as having type 1 diabetes since the ages of 6 and 2 years, respectively. This result is in contrast to the previously described carrier of the same mutation who was diagnosed with permanent neonatal diabetes. We identified a novel coding frameshift mutation and an intronic mutation in the INS gene leading to childhood-onset diabetes. INS mutations may result in various phenotypes, suggesting that additional mechanisms may be involved in the pathogenesis and clinical manifestation of diabetes.
authors.affiliation: Department of Pediatrics, Charles University in Prague, 2nd Faculty of Medicine and University Hospital Motol, Prague, CZ-150 06, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Dusatkova
authors.affiliation: Department of Pediatrics, Charles University in Prague, 2nd Faculty of Medicine and University Hospital Motol, Prague, CZ-150 06, Czech Republic. Electronic address: petra.dusatkova@lfmotol.cuni.cz.
authors.forename: Petra
authors.initials: P
authors.lastname: Dusatkova
authors.affiliation: Department of Pediatrics, Charles University in Prague, 3rd Faculty of Medicine and University Hospital Kralovske Vinohrady, Prague, CZ-100 34, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Vosahlo
authors.affiliation: Department of Pediatrics, Charles University in Prague, 2nd Faculty of Medicine and University Hospital Motol, Prague, CZ-150 06, Czech Republic.
authors.forename: Klara
authors.initials: K
authors.lastname: Vesela
authors.affiliation: Department of Pediatrics, Charles University in Prague, 2nd Faculty of Medicine and University Hospital Motol, Prague, CZ-150 06, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Cinek
authors.affiliation: Department of Pediatrics, Charles University in Prague, 2nd Faculty of Medicine and University Hospital Motol, Prague, CZ-150 06, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Lebl
authors.affiliation: Department of Pediatrics, Charles University in Prague, 2nd Faculty of Medicine and University Hospital Motol, Prague, CZ-150 06, Czech Republic.
authors.forename: Stepanka
authors.initials: S
authors.lastname: Pruhova
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D002096:C-Peptide / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005190:Family; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D006801:Humans; D007328:Insulin / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017422:Sequence Analysis, DNA
chemical_list: D002096:C-Peptide; D007328:Insulin
keywords: Diabetes; MODY; insulin gene; mutation