Molecular genetics of diabetes mellitus in Chinese subjects: identification of mutations in glucokinase and hepatocyte nuclear factor-1alpha genes in patients with early-onset type 2 diabetes mellitus/MODY.
OBJECTIVE
To examine the prevalence of identified MODY-related genes in Chinese subjects with early onset Type 2 diabetes mellitus and a positive family history of diabetes and to look for possible associations between the gene mutations and the development of diabetes.


METHODS
Ninety-two unrelated Chinese subjects with diabetes diagnosed before the age of 40 years who had a positive family history of diabetes were screened for mutations in hepatocyte nuclear factors (HNF-1alpha and HNF-4alpha) and glucokinase genes by direct sequencing. The family members of patients with mutations and 100 healthy controls were also examined.


RESULTS
Mutations in the HNF-1alpha and the glucokinase genes were found in 5% and 3% of the diabetic subjects, respectively but no mutations were found in the coding region of the HNF-4alpha gene. Three mutations found in the glucokinase gene were novel missense mutations (I110T, A119D and G385V). The mutations in the HNF-1alpha gene were also new and included four missense mutations (G20R, R203H, S432C, I618M) and one splice acceptor site mutation (IVS2nt-1G-->A). Patients with mutations in these genes were clinically heterogeneous with respect to phenotype and basal pancreatic beta cell function.


CONCLUSIONS
Genetic factors such as mutations in the HNF-1alpha and glucokinase genes may be important in the development of diabetes in Chinese people, especially when the disease is of early onset.
Ng
M C
MC
Department of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong. b770727@mailserv.cuhk.edu.hk
Cockburn
B N
BN
Lindner
T H
TH
Yeung
V T
VT
Chow
C C
CC
So
W Y
WY
Li
J K
JK
Lo
Y M
YM
Lee
Z S
ZS
Cockram
C S
CS
Critchley
J A
JA
Bell
G I
GI
Chan
J C
JC
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D019943:Amino Acid Substitution; D044466:Asian People / Q000235:genetics*; D002648:Child; D002681:China; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D005190:Family; D005260:Female; D005941:Glucokinase / Q000235:genetics*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007438:Introns; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D009687:Nuclear Proteins; D017354:Point Mutation; D014157:Transcription Factors / Q000235:genetics*
D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D005941:Glucokinase