Hepatocyte Nuclear Factor-1α Gene Inactivation: Cosegregation between Liver Adenomatosis and Diabetes Phenotypes in Two Maturity-Onset Diabetes of the Young (MODY)3 Families

Abstract

Heterozygous germline mutations of the hepatocyte nuclear factor (HNF)-1 alpha are associated with maturity-onset diabetes of the young (MODY)3. Recently, the biallelic inactivation of the HNF-1 alpha gene was reported in liver adenomas. We show the occurrence of liver adenomatosis in six MODY3-affected patients from two unrelated and large families. Liver adenomatosis was characterized by the presence of numerous adenomas within a normal hepatic parenchyma. The HNF-1 alpha hot-spot germline mutation P291fs was identified in the two probands and in 16 relatives from the two families. The six patients affected by liver adenomatosis and diabetes exhibited the mutation. The analysis of liver-cell tumors from two affected patients evidenced the biallelic inactivation of HNF-1 alpha. The familial screening confirmed the clinical heterogeneity of the liver phenotype, from silent liver adenomatosis to fatal hemorrhage. These observations warrant the systematic screening for liver adenomatosis in MODY3 families to prevent its potentially deadly complications. Moreover, such screening may help to determine if a particular mutational spectrum of HNF-1 alpha is associated with liver adenomatosis and to establish its prevalence in this frequent form of diabetes in the young adult.

Liver transplantation for adenomatosis: European experience

“…Twenty-seven of the 49 (55%) patients were younger than 30 years. We obtained information for maturity onset diabetes of the young (MODY) 3 diabetes (23)(24)(25) for 2 patients, and 2 patients had a family history of adenomatosis, including 2 sisters in this study. Sixteen (33%) patients had GSD type IA in this study.…”

Genotype–phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC

“…We previously showed that germline HNF1␣ mutations predispose to liver adenomatosis and MODY3. [5][6][7] These observations suggested that relatives of patients presenting germline HNF1␣ mutation should be investigated for familial liver adenomatosis. Other genetic predispositions may be identified, particularly to explain the occurrence of multiple adenomas in patients.…”

“…2 In 1978, Foster and collaborators described another clinical entity, which was the first case of familial adenomatosis associated with diabetes, 3 later confirmed by others. [4][5][6][7] Some small HA may regress after withdrawal of oral contraceptives; however, they usually remain stable, or increase in size. They may bleed, or rarely, undergo malignant transformation.…”

“…Mutations of the TCF1 gene inactivating the hepatocyte nuclear factor 1␣ (HNF1␣) transcription factor, were identified in half of HA cases, 5 and most frequently both allelic mutations were somatic. Patients with an inherited mutation in 1 allele of HNF1␣ may develop maturity-onset diabetes of the young type 3 13 (MODY3, OMIM#600496) and familial liver adenomatosis, when the second allele is inactivated in hepatocytes by somatic mutation or chromosome deletion [5][6][7] …”

“…Among the 96 included cases, 18 were previously described. 5,7 For each case, a representative part of the principal nodule, as well as of the nontumoral liver, was immediately frozen in liquid nitrogen and stored at Ϫ80°C until used for molecular studies. When multiple nodules were present, one representative lesion was selected, and the same lesion was analyzed by molecular biology and reviewed morphologically.…”