The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3.
OBJECTIVE
The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-alpha (HNF1A) gene mutation.


METHODS
We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations between the genotype and age at diagnosis of diabetes.


RESULTS
Missense mutations prevailed in the dimerization and DNA-binding domains (74%), while truncating mutations were predominant in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1- 6, thus affecting the three HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations (18 vs. 22 years, P = 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than those affecting the transactivation domain (20 vs. 30 years, P = 10(-4)). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P = 0.03).


CONCLUSIONS
These data show that part of the variability of the clinical expression in MODY3 patients may be explained by the type and the location of HNF1A mutations. These findings should be considered in studies for the search of additional modifier genetic factors.
Bellanné-Chantelot
Christine
C
Département de Génétique, Groupe Hospitalier Pitié-Salpétrière, Bât 6 rue Lapeyronie, 47/83 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France. christine.bellanne-chantelot@psl.aphp.fr
Carette
Claire
C
Riveline
Jean-Pierre
JP
Valéro
René
R
Gautier
Jean-François
JF
Larger
Etienne
E
Reznik
Yves
Y
Ducluzeau
Pierre-Henri
PH
Sola
Agnès
A
Hartemann-Heurtier
Agnès
A
Lecomte
Pierre
P
Chaillous
Lucy
L
Laloi-Michelin
Marie
M
Wilhem
Jean-Marie
JM
Cuny
Pierre
P
Duron
Françoise
F
Guerci
Bruno
B
Jeandidier
Nathalie
N
Mosnier-Pudar
Helen
H
Assayag
Michel
M
Dubois-Laforgue
Danièle
D
Velho
Gilberto
G
Timsit
José
J
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D017398:Alternative Splicing; D019943:Amino Acid Substitution; D001665:Binding Sites; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D014644:Genetic Variation; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D020125:Mutation, Missense; D017384:Sequence Deletion
C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha