Hepatocyte nuclear factor-1beta gene deletions--a common cause of renal disease.
BACKGROUND
Hepatocyte nuclear factor-1beta (HNF-1beta) is a critical transcription factor in pancreatic and renal development. Our previous report identified HNF-1beta mutations in 23/160 patients with unexplained renal disease. The most common phenotype is renal cysts, which is frequently associated with early-onset diabetes in the renal cysts and diabetes (RCAD) syndrome. HNF-1beta gene deletions have recently been shown to cause renal malformations and early-onset diabetes.


METHODS
We developed a multiplex ligation-dependent probe amplification (MLPA) assay for HNF-1beta gene dosage analysis and tested patients with unexplained renal disease in whom mutations had not been found by sequencing.


RESULTS
Whole HNF-1beta gene deletions were detected in 15/133 probands. Renal cysts were present in 13/15, including three with glomerulocystic kidney disease and one with cystic renal dysplasia. Renal function ranged from normal to transplantation aged 3 years. Ten probands had diabetes (nine having RCAD). In addition, four had abnormal liver function tests, two showed pancreatic atrophy and 3/10 female probands had uterine malformations. Whole HNF-1beta gene deletions are a common cause of developmental renal disease, particularly renal cystic disease with or without diabetes.


CONCLUSIONS
The phenotype associated with deletions or coding region/splicing mutations is very similar suggesting that haploinsufficiency is the underlying mechanism. Patients with features suggestive of the HNF-1beta clinical phenotype should be tested for mutations both by sequence and dosage analysis.
Edghill
Emma L
EL
1Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK.
Oram
Richard A
RA
Owens
Martina
M
Stals
Karen L
KL
Harries
Lorna W
LW
Hattersley
Andrew T
AT
Ellard
Sian
S
Bingham
Coralie
C
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003928:Diabetic Nephropathies / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree
D051539:Hepatocyte Nuclear Factor 1-beta