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Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease

Lookup NU author(s): Dr Kyle Thompson, Professor Bobby McFarlandORCiD, Professor Robert Taylor



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2022 The Authors. Mitochondrial disorders are clinically and genetically heterogeneous, with variants in mitochondrial or nuclear genes leading to varied clinical phenotypes. TAMM41 encodes a mitochondrial protein with cytidine diphosphate-diacylglycerol synthase activity: an essential early step in the biosynthesis of phosphatidylglycerol and cardiolipin. Cardiolipin is a mitochondria-specific phospholipid that is important for many mitochondrial processes. We report three unrelated individuals with mitochondrial disease that share clinical features, including lethargy at birth, hypotonia, developmental delay, myopathy, and ptosis. Whole exome and genome sequencing identified compound heterozygous variants in TAMM41 in each proband. Western blot analysis in fibroblasts showed a mild oxidative phosphorylation (OXPHOS) defect in only one of the three affected individuals. In skeletal muscle samples, however, there was severe loss of subunits of complexes I–IV and a decrease in fully assembled OXPHOS complexes I–V in two subjects as well as decreased TAMM41 protein levels. Similar to the tissue-specific observations on OXPHOS, cardiolipin levels were unchanged in subject fibroblasts but significantly decreased in the skeletal muscle of affected individuals. To assess the functional impact of the TAMM41 missense variants, the equivalent mutations were modeled in yeast. All three mutants failed to rescue the growth defect of the Δtam41 strains on non-fermentable (respiratory) medium compared with wild-type TAM41, confirming the pathogenicity of the variants. We establish that TAMM41 is an additional gene involved in mitochondrial phospholipid biosynthesis and modification and that its deficiency results in a mitochondrial disorder, though unlike families with pathogenic AGK (Sengers syndrome) and TAFAZZIN (Barth syndrome) variants, there was no evidence of cardiomyopathy.

Publication metadata

Author(s): Thompson K, Bianchi L, Rastelli F, Piron-Prunier F, Ayciriex S, Besmond C, Hubert L, Barth M, Barbosa IA, Deshpande C, Chitre M, Mehta SG, Wever EJM, Marcorelles P, Donkervoort S, Saade D, Bonnemann CG, Chao KR, Cai C, Iannaccone ST, Dean AF, McFarland R, Vaz FM, Delahodde A, Taylor RW, Rotig A

Publication type: Article

Publication status: Published

Journal: Human Genetics and Genomics Advances

Year: 2022

Volume: 3

Issue: 2

Print publication date: 14/04/2022

Online publication date: 04/03/2022

Acceptance date: 25/02/2022

Date deposited: 29/03/2022

ISSN (electronic): 2666-2477

Publisher: Cell Press


DOI: 10.1016/j.xhgg.2022.100097


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Funder referenceFunder name
203105/Z/16/ZWellcome Trust
MR/S005021/1Medical Research Council (MRC)
The Lily Foundation
UK NHS Specialist Commissioners
UK NIHR Biomedical Research Center for Aging and Age-Related Disease Award