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-1 beta
Th. Lindner et al., 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-1 beta, HUM MOL GEN, 8(11), 1999, pp. 2001-2008
Mutations in the homeodomain-containing transcription factor hepatocyte nuc
lear factor (HNF)-1 beta are the cause of one form of maturity-onset diabet
es of the young (MODY), type 5 (MODY5), We have studied a Norwegian family,
N5, with a syndrome of mild diabetes, progressive non-diabetic renal disea
se and severe genital malformations, The sequence of the HNF-1 beta gene (T
CF2) 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-K161
del), This deletion is located in the pseudo-POU region of HNF-1 beta, a re
gion implicated in the specificity of DNA binding, Functional studies of R1
37-K161del HNF-1 beta revealed that it could not bind an HNF-1 target seque
nce or stimulate transcription of a reporter gene indicating that this is a
loss-of-function mutation, The R137-K161del allele co-segregated with diab
etes and renal disease in pedigree N5, In addition, two of four female carr
iers with this mutation had vaginal aplasia and rudimentary uterus (Mulleri
an aplasia), These studies strongly suggest that heterozygous mutations in
the HNF-1b gene are associated with a syndrome characterized by MODY and se
vere, non-diabetic renal disease, Moreover, the presence of internal genita
l malformations in two females suggests that additional clinical features m
ay be associated with HNF-1 beta mutations.