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Schlieben, L.D. ; Achleitner, M.T.* ; Bourke, B.* ; Diesner, M.* ; Feichtinger, R.G.* ; Fichtner, A.* ; Flechtenmacher, C.* ; Hadzic, N.* ; Hegarty, R.* ; Heilos, A.* ; Janecke, A.* ; Konstantopoulou, V.* ; Lenz, D.* ; Mayr, J.A.* ; Müller, T.* ; Prokisch, H. ; Vogel, G.F.*

Missense variants in the TRPMr7 α-kinase domain are associated with recurrent pediatric acute liver failure.

Hepat. Commun. 8:e0598 (2024)

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BACKGROUND: Pediatric acute liver failure (PALF) is a rare and life-threatening condition. In up to 50% of PALF cases, the underlying etiology remains unknown during routine clinical testing. This lack of knowledge complicates clinical management and liver transplantation decisions. Recently, whole-exome sequencing has identified genetic disorders in a large number of cases without specific laboratory biomarkers or metabolic fingerprints. METHODS: We describe how further analysis of whole-exome sequencing data combined with proteomic analyses in 5 previously unsolved PALF patients, where no pathogenic variants in genes previously associated with acute liver failure were identified, revealed rare biallelic variants in transient receptor potential cation channel subfamily M member 7 (TRPM7). RESULTS: We establishe TRPM7 as a novel disease gene for PALF. Yet, the cation channel kinase TRPM7 has not been associated with any Mendelian disorder. No homozygous loss-of-function variants were found in in-house exomes or publicly available databases. Rare biallelic TRPM7-variants were significantly enriched in the PALF cohort compared with a pediatric control cohort. Viral infections preceded the majority of PALF episodes. Recurrent PALF episodes characterized the disease course with rapid progression, leading to early death in 3 cases. Proteomic analyses of patient fibroblasts unveiled significantly reduced TRPM7 protein levels, indicative of functional impairment. Severely reduced Mg2+ levels in one individual with a mutation in the channel domain suggests a potential interaction between disturbed Mg2+ homeostasis and PALF. The consistent presence of mutations in the TRPM7 protein-kinase-domain across all patients suggests its specific relevance in PALF. CONCLUSIONS: Our data extend the genetic spectrum of recurrent PALF and prompt consideration of TRPM7 in children with unexplained liver failure.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords pediatric acute liver failure; TRPM7; whole-exome sequencing; Position Paper; Children; Cation; Hypomagnesemia; Management; Mutations; Diagnosis; Efficient; Etiology; Robust

ISSN (print) / ISBN 2471-254X

e-ISSN 2471-254X

Journal Hepatology communications

Quellenangaben Volume: 8, Issue: 12, Article Number: e0598

Publisher Wiley

Publishing Place Hoboken, NJ

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Neurogenomics (ING)

Grants EJP RD project GENOMIT (Austrian Science Fund FWF)
BMBF (German Federal Ministry of Education and Research) through the mitoNET German Network for Mitochondrial Diseases