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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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