A case report with functional characterization of a HNF1B mutation (P.Leu168Pro) causing MODY5

Kei Yoshida, Yuichi Mushimoto, Kanako Tanase-Nakao, Kazuhisa Akiba, Kanako Ishii, Tatsuhiko Urakami, Shigetaka Sugihara, Toru Kikuchi, Maki Fukami, Satoshi Narumi

研究成果: Article査読


We previously performed next-generation sequencing-based genetic screening in patients with autoantibodynegative type 1 diabetes, and identified the p.Leu168Pro mutation in HNF1B. Here, we report the clinical course of the patient and the results of functional characterization of this mutation. The proband had bilateral renal hypodysplasia and developed insulin-dependent diabetes during childhood. The pathogenicity of Leu168Pro-HNF1B was evaluated with three-dimensional structure modeling, Western blotting, immunofluorescence analysis and luciferase reporter assays using human embryonic kidney 293 cells. Three-dimensional structure modeling predicted that the Leu168 residue is buried in the DNA-binding Pit-Oct-Unc-specific (POUS) domain and forms a hydrophobic core. Western blotting showed that the protein expression level of Leu168Pro-HNF1B was lower than that of wild-type (WT) HNF1B. Immunofluorescence staining showed that both WT- and Leu168Pro-HNF1B were normally localized in the nucleus. The cells transfected with WT-HNF1B exhibited 5-fold higher luciferase reporter activity than cells transfected with an empty vector. The luciferase activities were comparable between WT-HNF1B/Leu168Pro-HNF1B and WT-HNF1B/empty vector co-transfection. In conclusion, Leu168Pro is a protein-destabilizing HNF1B mutation, and the destabilization is likely due to the structural changes involving the hydrophobic core of POUS. The disease-causing Leu168Pro HNF1B mutation is a loss-of-function mutation without a dominant-negative effect.

ジャーナルclinical pediatric endocrinology
出版ステータスPublished - 2021 10月

ASJC Scopus subject areas

  • 小児科学、周産期医学および子どもの健康
  • 内分泌学、糖尿病および代謝内科学
  • 内分泌学


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