Isomers of the TCF1 gene encoding hepatocyte nuclear factor-1 alpha show differential expression in the pancreas and define the relationship between mutation position and clinical phenotype in monogenic diabetes

Abstract

The generation of multiple transcripts by mRNA processing has the potential to moderate differences in gene expression both between tissues and at different stages of development. Where gene function is compromised by mutation, the presence of multiple isoforms may influence the resulting phenotype. Heterozygous mutations in the transcription factor hepatocyte nuclear factor-1 alpha (HNF1A or TCF1 gene) result in early-onset diabetes as a result of pancreatic beta-cell dysfunction. We investigated the expression of the three alternatively processed isoforms of the HNF1A gene and their impact on the phenotype associated with mutations. Real-time PCR demonstrated variation in tissue expression of HNF1A isomers: HNF1A(A), with the lowest transactivation activity compared with the truncated isoforms HNF1A(B) and HNF1A(C), is the major isomer in liver (54%) and kidney (67%) but not in adult pancreas (24%) and islets (26%). However, in fetal pancreas HNF1A(A) is the major transcript (84%), which supports developmental regulation of isomer expression. We examined whether the isomers affected by the mutation altered the diabetes phenotype in 564 subjects with 123 mutations in HNF1A. Mutations that affected only isomer HNF1A(A) (exons 8-10) were diagnosed later (25.5 years) than mutations affecting all three isomers (exons 1-6) (18.0 years) (P=0.006). This first genotype/phenotype relationship described for patients with HNF1A mutations is explained by isomer structure and not by either mutation type or functional domain. We conclude that all three isomers may be critical for beta-cell function and could play a role in both the developing and mature beta cell.

A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes

“…In one study lower age of diabetes diagnosis has been shown to be associated with missense mutations in exons expressed in all three isomers HNF1A(A), (B) and (C) [15]. In another study, lower age of diabetes diagnosis was associated with missense mutations within the dimerisation and DNA-binding domains [16].…”

Genetic and clinical characteristics of patients with HNF1A gene variations from the German–Austrian DPV database

“…Mutations affecting different isoforms have been associated with age at disease onset in certain studies; thus, isoforms may influence the phenotype of disease differently (6,7).…”

Clinical utility gene card for: Maturity-onset diabetes of the young

“…In contrast, patients with HNF1A truncating mutations are diagnosed at a median age of 20 years independently of the location of the mutation within HNF1A. 7,8 A similar correlation was observed with HNF4A mutations. 9…”