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.
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 (Müllerian 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.
Lindner
T H
TH
Howard Hughes Medical Institute, Department of Medicine, Biochemistry and Molecular Biology and Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA,
Njolstad
P R
PR
Horikawa
Y
Y
Bostad
L
L
Bell
G I
GI
Sovik
O
O
D000293:Adolescent; D000328:Adult; D002648:Child; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D016640:Diabetes, Gestational / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D005835:Genitalia / Q000002:abnormalities*; D006367:HeLa Cells; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics*; D052177:Kidney Diseases, Cystic / Q000235:genetics; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D011247:Pregnancy; D017434:Protein Structure, Tertiary / Q000235:genetics; D012326:RNA Splicing; D011993:Recombinant Fusion Proteins / Q000235:genetics; D017384:Sequence Deletion; D013577:Syndrome; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D014162:Transfection; D014621:Vagina / Q000002:abnormalities
D004268:DNA-Binding Proteins; C496495:HNF1B protein, human; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D051539:Hepatocyte Nuclear Factor 1-beta; D004247:DNA