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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.

Abstrakt

Nová mutace v inzulínovém genu vedoucí k posunu čtecího rámce u české rodiny s diabetem

Diabetologie, metabolismus, endokrinologie, výživa. 2014 ; 17 (Suppl. 1) : 39. (Abstrakta 50. diabetologických dnů, Luhačovice 10.–12. dubna 2014)

Diabetol. metab. endokrinol. výživ. (Print)
ISSN 1211-9326
Medvik
Zdroj

Diabetologické dny. 2014 ; 17 (Suppl. 1) : 39.

Medvik
Zdroj

Publikační typ
abstrakt z konference MeSH

Článek

Ancestral mutations may cause a significant proportion of GCK-MODY

Pediatric diabetes. 2012 ; 13 (6) : 489-498.

Pediatr Diabetes
ISSN 1399-5448
Medvik
Zdroj

BACKGROUND: Although the literature indicates that ancestral mutations in the glucokinase (GCK) gene are rare, we have detected a high frequency of four prevalent mutations that together are responsible for over one third of the GCK mutations in our Czech National Register of monogenic diabetes. Therefore, we studied their potential ancestral origin in our and neighbouring Polish populations. METHODS: We analysed the lineage of four mutations in the GCK gene - p.Glu40Lys (21 apparently unrelated families), p.Leu315His (15 families), p.Gly318Arg (26 families), and p.Val33Ala (10 families) - using genotypes of 16 single nucleotide polymorphisms that span a 14 Mb region around the gene. Haplotypes were reconstructed using Phase and Haploview programmes, and their age was estimated using dmle+. RESULTS: We found strong evidence that supports ancestral origin of three of the four mutations: the p.Glu40Lys mutation was associated with an 11-marker long conserved haplotype, the p.Leu315His mutation was associated with a 7-marker haplotype, and the p.Gly318Arg mutation was associated with an 8-marker haplotype. None of these haplotypes were detected in the general population with a frequency >0.5%. The ages of the mutations were roughly estimated to be between 82 and 110 generations old (95% credible sets 65-151). The fourth prevalent mutation, p.Val33Ala, lacked statistically significant evidence for the founder effect, although there were some indications for its common origin. CONCLUSIONS: The large proportion of families carrying three ancestral mutations in GCK indicates that the previously assumed rarity of the founder effect with regard to GCK-maturity onset diabetes of the young (MODY) should be reconsidered.