title: In vitro and pathological investigations of MODY5 with the R276X-HNF1beta (TCF2) mutation.
abstract: Maturity-onset diabetes of the young type 5 (MODY5) is caused by mutation of hepatocyte nuclear factor 1beta (HNF1 beta) (TCF2) gene, resulting in a wide range of phenotypes including diabetes and renal abnormalities, but little is known about the pathogenesis of the clinical spectrum. We describe a 27-year-old Japanese male with the MODY phenotype including an atrophic kidney and multiple renal cysts. Genetic analysis revealed the patient to be heterozygous for a nonsense mutation in codon 276 of the HNF1beta gene (CGA or Arginine to TGA or stop codon; R276X). To clarify the pathophysiological relevance of this mutation, we conducted an in vitro study monitoring human C-peptide secretion after transfecting both the HNF1beta mutant cDNA and preproinsulin cDNA into a murine beta cell line, MIN6. Functional studies of the transformed MIN6 cells indicated that expression of the R276X caused a significant decrease in glucose-stimulated insulin secretion but no change in either KCl-stimulated or basal insulin secretion. These results suggest that the R276X functions in a negative manner in regard to metabolic responses of insulin secretion in beta cells. Analysis with light and electron microscopy on biopsied kidney specimens suggested that the origin of the cysts might be glomeruli but the primary lesion could be tubules.
authors: Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.
authors: Kei
authors: K
authors: Fujimoto
authors: Takashi
authors: T
authors: Sasaki
authors: Yoshito
authors: Y
authors: Hiki
authors: Masami
authors: M
authors: Nemoto
authors: Yasunori
authors: Y
authors: Utsunomiya
authors: Takashi
authors: T
authors: Yokoo
authors: Nozomu
authors: N
authors: Nakai
authors: Toya
authors: T
authors: Ohashi
authors: Tatsuo
authors: T
authors: Hosoya
authors: Yoshikatsu
authors: Y
authors: Eto
authors: Naoko
authors: N
authors: Tajima
mesh_terms: D000328:Adult; D017668:Age of Onset; D001120:Arginine / Q000235:genetics; D002096:C-Peptide / Q000378:metabolism; D002478:Cells, Cultured; D018389:Codon, Nonsense; D003924:Diabetes Mellitus, Type 2 / Q000145:classification / Q000150:complications / Q000235:genetics*; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000378:metabolism; D008297:Male; D010375:Pedigree; D007690:Polycystic Kidney Diseases / Q000150:complications / Q000473:pathology; D014162:Transfection
chemical_list: D002096:C-Peptide; D018389:Codon, Nonsense; C496495:HNF1B protein, human; D051539:Hepatocyte Nuclear Factor 1-beta; D001120:Arginine