Autosomal inheritance of diabetes in two families characterized by obesity and a novel H241Q mutation in NEUROD1.
BACKGROUND
The aim of the study was to search for mutations in the NEUROD1 and IPF-1 genes in patients with clinical characteristics of maturity-onset diabetes of the young (MODY) but with no mutations in the HNF-4A (MODY1), GCK (MODY2) and TCF1 (MODY3) genes.


METHODS
We studied 30 unrelated Czech probands with a clinical diagnosis of MODY (median age at testing, 18 yr; median age at the recognition of hyperglycaemia, 16 yr). The promoter, exons and exon/intron boundaries of the NEUROD1 and IPF-1 genes were examined by polymerase chain reaction-denaturing high performance liquid chromatography and direct sequencing.


RESULTS
While no mutations were found in the IPF-1 gene, a novel H241Q substitution of NEUROD1 gene was identified in two unrelated families. In the first proband, the H241Q mutation led to early diagnosed (20 yr) hyperglycaemia followed by development of diabetic microvascular complications by the age of 32 yr. The second proband suffered from slowly progressing hyperglycaemia detected at the age of 30 yr. Affected members of both families were obese. The overall prevalence of the variant among the general population was 4 of 13 568 chromosomes.


CONCLUSIONS
We report a novel disease-associated variant in NEUROD1 identified among a set of MODYX families. The variant seems to precipitate type-2-like diabetes in excessively obese individuals.
Gonsorcíková
Lucie
L
Department of Paediatrics, Second Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
Průhová
Stepánka
S
Cinek
Ondrej
O
Ek
Jakob
J
Pelikánová
Terezie
T
Jørgensen
Torben
T
Eiberg
Hans
H
Pedersen
Oluf
O
Hansen
Torben
T
Lebl
Jan
J
D000293:Adolescent; D000328:Adult; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D009765:Obesity / Q000150:complications; D015534:Trans-Activators / Q000235:genetics*; D055815:Young Adult
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D015534:Trans-Activators; C093970:NEUROD1 protein, human; C084010:pancreatic and duodenal homeobox 1 protein