Genetic variants of hepatocyte nuclear factor-1b in Chinese young-onset diabetic patients with nephropathy W.Y. So a, *, Maggie C.Y. Ng a , Yukio Horikawa b , Pal R. Njølstad b , June K.Y. Li a , Ronald C.W. Ma a , Graeme I. Bell b , Juliana C.N. Chan a a Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China b Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA Received 16 April 2002; received in revised form 29 June 2002; accepted 16 August 2002 Abstract Background: In Hong Kong, the prevalence of diabetes is estimated to be 2% in the young population. In the diabetic population, 30% of patients have diagnosis before the age of 40 years. Besides, 30% of young diabetic patients have varying degrees of albuminuria [Janus et al., 2000; Cockram et al., 1993; Chan et al., 1995]. Mutations in the gene encoding the hepatocyte nuclear factor (HNF)-1b are associated with a subtype of maturity-onset diabetes of the young (MODY 5) characterized by urogenital abnormalities. We examined 74 unrelated Chinese subjects with young-onset diabetes complicated by nephropathy for variants in this gene. Methods: The HNF-1b gene was screened by direct sequencing and the functional properties of wild-type and mutant proteins were analyzed by transactivation analysis. Results: A novel variant in exon 3 (E260D) was found in one patient. Extended family analysis revealed four other siblings carrying this variant. One subject had diabetes and another had impaired glucose tolerance. Another sibling had microalbuminuria but normal glucose tolerance. Transfection studies showed insignificant differences in transactivation ability between wild-type and mutated HNF-1b. A silent polymorphism Q378Q was identified in another unrelated subject. Conclusions: These results suggest genetic variants in HNF-1b are not a common cause of young-onset diabetes or diabetic nephropathy in Chinese, but may modify disease manifestation and progression. Other potential candidate genes should be looked for to account for the high prevalence of young-onset diabetes and nephropathy in this population. D 2003 Elsevier Inc. All rights reserved. Keywords: Genetics; Diabetes; HNF-1b; Maturity-onset diabetes of young; Nephropathy; Transcription; Chinese 1. Introduction Recent studies have identified at least six genes respons- ible for maturity-onset diabetes of the young (MODY) characterized by autosomal dominant inheritance, early onset (usually before 25 years of age), and a primary defect in pancreatic b-cell function. Apart from MODY 2, due to mutations in glucokinase gene, the other forms of MODY are due to heterozygous mutations in transcription factors mainly belonging to the hepatocyte nuclear factor (HNF) family (Fajans, Bell, & Polonsky, 2001). These transcription factors form a network with HNF-1b function- ing as homo- or heterodimers with HNF-1a (Rey-Campos, Chouard, Yaniv, & Cereghini, 1991) and they are expressed sequentially in renal tubules with possible roles in various critical stages of development of renal tubules (Cereghini, Ott, Power, & Maury, 1992). Against this background, there is marked heterogeneity in the phenotypes of patients with mutations in different MODY genes in terms of metabolic and renal manifestations. Mutations in HNF-1b are associ- ated with MODY5 (Horikawa et al., 1997), characterized by mild diabetes but increased susceptibility to severe renal disease and other urogenital malformations. Knock-out mice model shows that deficiency of HNF-1b is associated with pancreatic b-cell and renal dysfunction (Bingham et al., 2000; Horikawa et al., 1997; Lindner et al., 1999; Tomura et al., 1999; Weng et al., 2000). On the other hand, patients with mutations in HNF-1a causing MODY3 have subtle renal disease with a low renal threshold for glucose (Menzel et al., 1998). Two epidemiological studies have shown that the pre- valence of diabetes is reaching epidemic proportion among 1056-8727/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1056-8727(02)00221-0 * Corresponding author. Tel.: +852-2632-3138; fax: +852-2632-3108. E-mail address: wingyeeso@cuhk.edu.hk (W.Y. So). Journal of Diabetes and Its Complications 17 (2003) 369 – 373