A Single Nucleotide Variant in HNF-1β is Associated with Maturity-Onset Diabetes of the Young in a Large Chinese Family.
BACKGROUND
Maturity-onset diabetes of the young (MODY) is a heterogeneous entity of monogenic disorders characterized by autosomal dominant inheritance. Eleven genes were related, including HNF4α, GCK, HNF1α, IPF1, and HNF-1β, and various mutations are being reported.


METHODS
To help the overall understanding of MODY-related pathologic mutations, we studied a large MODY family found in 2012, in Shandong, China, which contained 9 patients over 3 generations. DNA was extracted from the periphery blood samples of (i) 9 affected members, (ii) 17 unaffected members, and (iii) 1000 healthy controls. Three pooled samples were obtained by mixing equal quantity of DNA of each individual within the each group. Totally 400 microsatellite markers across the whole genome were genotyped by capillary electrophoresis. The known MODY-related gene near the identified marker was sequenced to look for putative risk variants.


RESULTS
Allelic frequency of marker D17S798 on chromosome 17q11.2 were significantly different (P<0.001) between the affected vs. unaffected members and the affected vs. healthy controls, but not between the unaffected members vs. healthy controls. MODY5-related gene, hepatocyte nuclear factor-1β (HNF-1β) on 17q12 near D17S798 became the candidate gene. A single nucleotide variant (SNV) of C77T in the non-coding area of exon 1 of HNF-1β was found to be related to MODY5.


CONCLUSIONS
This novel SNV of HNF-1β contributes to the diabetes development in the family through regulating gene expression most likely. The findings help presymptomatic diagnosis, and imply that mutations in the non-coding areas, as well as in the exons, play roles in the etiology of MODY.
Key Laboratory for Tumor Immunity and Genetic Engineering of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Peng
P
Zhou
Key Laboratory for Tumor Immunity and Genetic Engineering of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Ran
R
Wei
Shandong Institute of Endocrine and Metabolic Disease, Jinan, Shandong, China.
Zhenkui
Z
Guo
Zibo Center for Disease Control and Prevention, Zibo, Shandong, China.
Haining
H
Zhu
Dept. of Psychiatry, University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region (H.K.S.A.R.), China.
Desmond
D
Campbell
Dept. of Psychiatry, University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region (H.K.S.A.R.), China.
Qi
Q
Li
Key Laboratory for Tumor Immunity and Genetic Engineering of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Xiaoqun
X
Xu
Key Laboratory for Tumor Immunity and Genetic Engineering of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Junfu
J
Wang
Key Laboratory for Tumor Immunity and Genetic Engineering of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Meng
M
Luan
Key Laboratory for Tumor Immunity and Genetic Engineering of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Xing
X
Chen
Key Laboratory for Tumor Immunity and Genetic Engineering of Shandong Province, Institute of Basic Medicine, Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Gang
G
Chen
Hepatic nuclear factor 1 beta (HNF1β); Maturity-onset diabetes of the young (MODY); Maturity-onset diabetes of the young type 5 (MODY5)