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HNF1B-associated renal and extra-renal disease—an expanding clinical spectrum

Key Points

  • Heterozygous mutations in the gene encoding the transcription factor HNF1B result in a multi-system disorder and are the most common known monogenic cause of developmental renal disease

  • HNF1B mutations comprise base substitutions, small insertions–deletions, or whole-gene deletions; however, no evidence exists for a genotype–phenotype correlation

  • HNF1B-associated disease exhibits autosomal dominant inheritance; however, mutations and whole-gene deletions can occur spontaneously so family history of renal disease or diabetes mellitus may be absent

  • HNF1B is expressed in multiple fetal tissues and has an important role during several stages of nephrogenesis, including ureteric bud branching and tubular development

  • HNF1B-associated renal phenotypes are variable and include isolated bilateral hyperechogenic kidneys on prenatal ultrasonography; cysts; hypoplasia; single, horseshoe and duplex kidneys; collecting system abnormalities; bilateral hydronephrosis; and hyperuricaemic nephropathy

  • Electrolyte abnormalities include hypomagnesaemia and hyperuricaemia; extra-renal phenotypic features include early-onset diabetes mellitus, pancreatic hypoplasia, genital tract malformations and abnormal liver function test results

Abstract

Heterozygous mutations in the gene that encodes the transcription factor hepatocyte nuclear factor 1β (HNF1B) represent the most common known monogenic cause of developmental kidney disease. Renal cysts are the most frequently detected feature of HNF1B-associated kidney disease; however, other structural abnormalities, including single kidneys and renal hypoplasia, and electrolyte abnormalities can also occur. Extra-renal phenotypes might also be observed; consequently, HNF1B-associated disease is considered a multi-system disorder. Other clinical features include early-onset diabetes mellitus, pancreatic hypoplasia, genital tract malformations, abnormal liver function and early-onset gout. Heterozygous mutations in the coding region or splice sites of HNF1B, and complete gene deletion, each account for 50% of all cases of HNF1B-associated disease, respectively, and often arise spontaneously. There is no clear genotype–phenotype correlation, consistent with haploinsufficiency as the disease mechanism. Data from animal models suggest that HNF1B has an important function during several stages of nephrogenesis; however, the precise signalling pathways remain to be elucidated. This Review discusses the genetics and molecular pathways that lead to disease development, summarizes the reported renal and extra-renal phenotypes, and identifies areas for future research in HNF1B-associated disease.

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Figure 1
Figure 2: Distribution of mutations within the gene that encodes hepatocyte nuclear factor 1β.

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Acknowledgements

The authors' research is supported by a Medical Research Council Clinical Training Fellowship (MR/J011630/1) to R.L.C., a National Institute for Health Research Senior Investigator award (NF-SI-0611-10219) to A.T.H. and a Wellcome Trust Senior Investigator award (098,395/Z/12/Z) to S.E. and A.T.H. The authors thank Kevin Colclough (Exeter Molecular Genetics Laboratory, UK) for his assistance in the preparation of Figure 2.

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R.L.C. and A.J.H. researched the data for the article. R.L.C., A.T.H., S.E. and C.B provided substantial contribution to discussions of the content. R.L.C. and A.J.H. contributed equally to writing the article. All authors contributed to review and/or editing of the manuscript before submission.

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Correspondence to Andrew T. Hattersley.

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HNF1B mutations and protein effects, as listed in the Human Gene Mutation Database (PDF 516 kb)

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Clissold, R., Hamilton, A., Hattersley, A. et al. HNF1B-associated renal and extra-renal disease—an expanding clinical spectrum. Nat Rev Nephrol 11, 102–112 (2015). https://doi.org/10.1038/nrneph.2014.232

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