The HNF1A mutant Ala180Val: Clinical challenges in determining causality of a rare HNF1A variant in familial diabetes

Diabetes Res Clin Pract. 2017 Nov;133:142-149. doi: 10.1016/j.diabres.2017.08.001. Epub 2017 Sep 1.


Aims: Heterozygous mutations in hepatocyte nuclear factor-1A (HNF1A) cause maturity-onset diabetes of the young type 3 (MODY3). Our aim was to compare two families with suspected dominantly inherited diabetes and a new HNF1A variant of unknown clinical significance.

Methods: The HNF1A gene was sequenced in two independently recruited families from the Norwegian MODY Registry. Both familes were phenotyped clinically and biochemically. Microsatellite markers around and within the HNF1A locus were used for haplotyping. Chromosomal linkage analysis was performed in one family, and whole-exome sequencing was undertaken in two affected family members from each family. Transactivation activity, DNA binding and nuclear localization of wild type and mutant HNF-1A were assessed.

Results: The novel HNF1A variant c.539C>T (p.Ala180Val) was found in both families. The variant fully co-segregated with diabetes in one family. In the other family, two subjects with diabetes mellitus and one with normal glucose levels were homozygous variant carriers. Chromosomal linkage of diabetes to the HNF1A locus or to other genomic regions could not be established. The protein functional studies did not reveal significant differences between wild type and variant HNF-1A. In each family, whole-exome sequencing failed to identify any other variant that could explain the disease.

Conclusions: The HNF1A variant p.Ala180Val does not seem to cause MODY3, although it may confer risk for type 2 diabetes mellitus. Our data demonstrate challenges in causality evaluation of rare variants detected in known diabetes genes.

Keywords: Genetics; HNF1A; MODY3; Type 2 diabetes mellitus.

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Amino Acid Sequence
  • Base Sequence
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Genetic Association Studies
  • Genetic Linkage
  • Genetic Predisposition to Disease
  • HeLa Cells
  • Hepatocyte Nuclear Factor 1-alpha / genetics*
  • Heterozygote
  • Humans
  • Male
  • Middle Aged
  • Mutation, Missense
  • Norway
  • Pedigree
  • Phenotype
  • Young Adult


  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha

Supplementary concepts

  • Maturity-Onset Diabetes of the Young, Type 3