Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases.
OBJECTIVE
Hepatocyte nuclear factor 1beta (HNF1beta) is a transcription factor that is critical for the development of kidney and pancreas. In humans, mutations in HNF1B lead to congenital anomalies of the kidney and urinary tract, pancreas atrophy, and maturity-onset diabetes of the young type 5 and genital malformations.


METHODS
We report HNF1B screening in a cohort of 377 unrelated cases with various kidney phenotypes (hyperechogenic kidneys with size not more than +3 SD, multicystic kidney disease, renal agenesis, renal hypoplasia, cystic dysplasia, or hyperuricemic tubulointerstitial nephropathy not associated with UMOD mutation).


RESULTS
We found a heterozygous mutation in 75 (19.9%) index cases, consisting of a deletion of the whole gene in 42, deletion of one exon in one, and small mutations in 32. Eighteen mutations were novel. De novo mutations accounted for 66% of deletions and 40% of small mutations. In patients who carried HNF1B mutation and for whom we were able to study prenatal ultrasonography (56 probands), isolated hyperechogenic kidneys with normal or slightly enhanced size were the more frequent (34 of 56) phenotype before birth. Various other prenatal renal phenotypes were associated with HNF1B mutations, at a lesser frequency. Diabetes developed in four probands. Hyperuricemia and hypomagnesemia, although not systematically investigated, were frequently associated.


CONCLUSIONS
This large series showed that the severity of the renal disease associated with HNF1B mutations was extremely variable (from prenatal renal failure to normal renal function in adulthood) and was not correlated with the genotype.
Heidet
Laurence
L
Service de Néphrologie Pédiatrique, Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte, Paris, France. laurence.heidet@nck.aphp.fr
Decramer
Stéphane
S
Pawtowski
Audrey
A
Morinière
Vincent
V
Bandin
Flavio
F
Knebelmann
Bertrand
B
Lebre
Anne-Sophie
AS
Faguer
Stanislas
S
Guigonis
Vincent
V
Antignac
Corinne
C
Salomon
Rémi
R
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D016009:Chi-Square Distribution; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D005865:Gestational Age; D005919:Glomerular Filtration Rate / Q000235:genetics; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D007668:Kidney / Q000002:abnormalities* / Q000000981:diagnostic imaging / Q000503:physiopathology; D007674:Kidney Diseases / Q000000981:diagnostic imaging / Q000235:genetics*; D008297:Male; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D012189:Retrospective Studies; D017384:Sequence Deletion; D012720:Severity of Illness Index; D016216:Ultrasonography, Prenatal
C496495:HNF1B protein, human; D051539:Hepatocyte Nuclear Factor 1-beta