Faculty Collaboration Database

Discovery of a MET -driven monogenic cause of steatotic liver disease. Hepatology 2025 Dec 01;82(6):1512-1522

Date

01/29/2025

Pubmed ID

39879586

DOI

10.1097/HEP.0000000000001249

Scopus ID

2-s2.0-85217105777 (requires institutional sign-in at Scopus site)

Abstract

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease affects about a third of adults worldwide and is projected soon to be the leading cause of liver cirrhosis. It occurs when fat accumulates in hepatocytes and can progress to metabolic dysfunction-associated steatohepatitis, liver cirrhosis, and HCC. Metabolic dysfunction-associated steatotic liver disease pathogenesis is believed to involve a combination of genetic and environmental risk factors. Single nucleotide polymorphisms have been implicated, but non-syndromic monogenic causes are lacking.

APPROACH AND RESULTS: We identified a novel genetic variant in a familial case of metabolic dysfunction-associated steatohepatitis and performed deep variant functional analysis, including protein modeling, dynamics, and cell-based assays to assess molecular mechanisms of dysfunction and altered cellular signaling. We analyzed exome sequencing data of 3904 individuals with steatotic liver disease (SLD) to identify additional cases and establish the link between specific gene variants and SLD diagnosis. We discovered and functionally validated the NM_000245.4:c.3505A>T; p.(Ile1169Phe) variant in the MET (mesenchymal-epithelial transition) kinase domain as a monogenic cause of SLD. Subsequently, we detected additional ultra-rare, previously uninterpreted, and likely deleterious variants in MET from screening sequencing data. Among individuals with confirmed SLD based on electronic record review, 1.1% (45/3904) had rare predicted deleterious MET variants. Eight of 45 (17.7%) individuals had predicted deleterious variants in the MET kinase domain confirmed to be functionally like the familial case variant.

CONCLUSIONS: We report the first germline nonmalignant rare MET -driven disease, a monogenic form of SLD.

Author List

Pinto E Vairo F, Zimmermann MT, Wagenknecht J, Jorge SD, Tian S, Vierkant RA, Luehrs AC, Milech de Assunção T, Mathison A, Atwal PS, Cao Y, Allen AM, Klee EW, Urrutia R, Lazaridis KN

Authors

Angela Mathison PhD Associate Professor in the Surgery department at Medical College of Wisconsin
Thiago Milech De Assuncao Research Scientist II in the Cell Biology Neurobiology and Anatomy department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin
Jessica B. Wagenknecht Bioinformatics Analyst II in the Mellowes Center for Genomic Sciences and Precision Medicine department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Associate Professor in the Data Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Fatty Liver
Female
Humans
Male
Middle Aged
Non-alcoholic Fatty Liver Disease
Pedigree
Polymorphism, Single Nucleotide
Proto-Oncogene Proteins c-met