Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases

Abstract

Background and objectives: 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.

Design, setting, participants, & measurements: 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.

Figure 1.

HNF1β protein and localization of the various mutations identified in this study. The N-terminal portion of the protein consists of a short dimerization domain (dim). The DNA-binding domain is characterized by a region distantly related to the POU box-specific domain and an atypical homeodomain structure. The residues required for HNF1β transactivation have been mapped to the carboxy-terminal region. Deletions are indicated by a solid line. *Novel mutation.

Figure 2.

Type of HNF1B mutation (□, deletion of the entire gene; , missense mutations; ■, truncating mutations) according to the renal phenotype in patients and affected relatives. 1, prenatal hyperechogenic kidneys; 2, hyperechogenic kidney diagnosed after birth; 3, MCD; 4, unilateral renal agenesis; 5, cystic disease; 6, renal hypoplasia; 7, tubulointerstitial nephritis; 8, pyeloureteral junction; 9, pelvic kidney; 10, lack of renal anomaly.

Figure 3.

Type of HNF1B mutation (deletion, missense mutations, truncating mutations) according to the GFR at last follow-up (■, GFR >80 ml/min per 1.73 m²; □, GFR <80 ml/min per 1.73 m²) and age at last follow-up (▧).