Genotype/phenotype relationships in HNF-4 alpha/MODY1 - Haploinsufficiencyis associated with reduced apolipoprotein(AII), apolipoprotein(CIII), lipoprotein(a), and triglyceride levels

Hepatocyte nuclear factor (HNF)-4 alpha is a transcription factor that play s an important role in regulation of gene expression in pancreatic beta-cel ls and in the liver. Heterozygous mutations in the HNF-4 alpha gene are res ponsible for maturity-onset diabetes of the young 1 (MODY1), which is chara cterized by pancreatic beta-cell-deficient insulin secretion. HNF-4 alpha i s a major transcriptional regulator of many genes expressed in the liver. H owever, no liver defect has been identified in individuals with HNF-4 alpha mutations. In this study we have identified HNF-4 alpha target genes that are mainly expressed in the liver, including alpha 1-antitrypsin, alpha 1-a ntichymotrypsin, 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-4 alpha/MODY1 RW pedigree (Q268X mutation), includ ing 12 diabetic patients with HNF-4 alpha mutations (D-HNF4(+/-)), 6 nondia betic subjects with HNF-4 alpha 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 signi ficantly reduced in HNF4(+/-) subjects (26.9, 19.8, 12.1, and 72.1 mg/dl, r espectively) 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-4 a lpha haploinsufficiency rather than hyperglycemia is the primary cause of d ecreased serum protein and triglyceride concentrations. Furthermore, we det ermined that genetic or environmental modifiers other than HNF-4 alpha do n ot appear to contribute to the observed decrease of HNF-4 alpha-regulated s erum proteins. This study demonstrates that a heterozygous HNF-4 alpha muta tion lends to an HNF-4 alpha-dependent hepatocyte secretory defect of liver -specific proteins.