Human Molecular Genetics, Vol 8, 2001-2008, Copyright © 1999 by Oxford University Press
TH Lindner, PR Njolstad, Y Horikawa, L Bostad, GI Bell and O Sovik
Mutations in the homeodomain-containing transcription factor hepatocyte
nuclear factor (HNF)-1beta are the cause of one form of maturity-onset
diabetes of the young (MODY), type 5 (MODY5). We have studied a Norwegian
family, N5, with a syndrome of mild diabetes, progressive non- diabetic
renal disease and severe genital malformations. The sequence of the
HNF-1beta gene ( TCF2 ) revealed a 75 bp deletion in exon 2 (409- 483del)
which would result in the synthesis of a protein lacking amino acids Arg137
to Lys161 (R137-K161del). This deletion is located in the pseudo-POU region
of HNF-1beta, a region implicated in the specificity of DNA binding.
Functional studies of R137-K161del HNF-1beta revealed that it could not
bind an HNF-1 target sequence or stimulate transcription of a reporter gene
indicating that this is a loss-of- function mutation. The R137-K161del
allele co-segregated with diabetes and renal disease in pedigree N5. In
addition, two of four female carriers with this mutation had vaginal
aplasia and rudimentary uterus (Mullerian aplasia). These studies strongly
suggest that heterozygous mutations in the HNF-1beta gene are associated
with a syndrome characterized by MODY and severe, non-diabetic renal
disease. Moreover, the presence of internal genital malformations in two
females suggests that additional clinical features may be associated with
HNF-1beta mutations.
ARTICLES
A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1beta
Howard Hughes Medical Institute, Department of Medicine, Biochemistry and Molecular Biology and Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA,
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