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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.
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
URL: https://doi.org/10.1016/j.xhgg.2022.100097
DOI: 10.1016/j.xhgg.2022.100097
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