title: Genotype/phenotype relationships in HNF-4alpha/MODY1: haploinsufficiency is associated with reduced apolipoprotein (AII), apolipoprotein (CIII), lipoprotein(a), and triglyceride levels.
abstract: Hepatocyte nuclear factor (HNF)-4alpha is a transcription factor that plays an important role in regulation of gene expression in pancreatic beta-cells and in the liver. Heterozygous mutations in the HNF-4alpha gene are responsible for maturity-onset diabetes of the young 1 (MODY1), which is characterized by pancreatic beta-cell-deficient insulin secretion. HNF-4alpha is a major transcriptional regulator of many genes expressed in the liver. However, no liver defect has been identified in individuals with HNF-4alpha mutations. In this study, we have identified HNF-4alpha target genes that are mainly expressed in the liver, including alpha1-antitrypsin, alpha1-antichymotrypsin, alpha-fetal protein, ceruloplasmin, IGF binding protein 1, transferrin, apolipoprotein(AI) [apo(AI)], apo(AII), apo(B), and apo(CIII). Serum levels of these proteins and Lp(a) and triglycerides were measured in 24 members of the HNF-4alpha/MODY1 RW pedigree (Q268X mutation), including 12 diabetic patients with HNF-4alpha mutations (D-HNF4+/-), 6 nondiabetic subjects with HNF-4alpha mutations (N-HNF4+/-), 6 normal relatives (N-HNF4+/+), 6 unrelated normal matched control subjects (N-HNF4+/+), and 12 matched diabetic (non-MODY1-5) patients (D-HNF4+/+). Serum levels of apo(AII), apo(CIII), lipoprotein(a) [Lp(a)], and triglyceride were significantly reduced in HNF4+/- subjects (26.9, 19.8, 12.1, and 72.1 mg/dl, respectively) compared with HNF4+/+ subjects (37.4, 26.5, 45.2, and 124.2 mg/dl, respectively) (P = 0.00001, P = 0.01, P = 0.00006, and P = 0.000003, respectively). This reduction was not found when apo(AII), apo(CIII), Lp(a), and triglyceride levels were compared in D-HNF4+/- versus N-HNF4+/- or in D-HNF4+/+ versus N-HNF4+/+ subjects, which indicates that HNF-4alpha haploinsufficiency rather than hyperglycemia is the primary cause of decreased serum protein and triglyceride concentrations. Furthermore, we determined that genetic or environmental modifiers other than HNF-4alpha do not appear to contribute to the observed decrease of HNF-4alpha-regulated serum proteins. This study demonstrates that a heterozygous HNF-4alpha mutation leads to an HNF-4alpha-dependent hepatocyte secretory defect of liver-specific proteins.
authors.affiliation: Laboratory of Metabolic Diseases, Rockefeller University, New York, New York 10021, USA.
authors.forename: D Q
authors.initials: DQ
authors.lastname: Shih
authors.forename: H M
authors.initials: HM
authors.lastname: Dansky
authors.forename: M
authors.initials: M
authors.lastname: Fleisher
authors.forename: G
authors.initials: G
authors.lastname: Assmann
authors.forename: S S
authors.initials: SS
authors.lastname: Fajans
authors.forename: M
authors.initials: M
authors.lastname: Stoffel
mesh_terms: D000328:Adult; D016633:Apolipoprotein A-II / Q000097:blood; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C / Q000097:blood; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D017270:Lipoprotein(a) / Q000097:blood; D008297:Male; D009154:Mutation; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*; D014280:Triglycerides / Q000097:blood
chemical_list: D016633:Apolipoprotein A-II; D053305:Apolipoprotein C-III; D001056:Apolipoproteins C; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D004268:DNA-Binding Proteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D017270:Lipoprotein(a); C403128:MLX protein, human; D010750:Phosphoproteins; D014157:Transcription Factors; D014280:Triglycerides