Journal article
Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease
HGG advances, Vol.3(2), pp.100097-100097
04/14/2022
DOI: 10.1016/j.xhgg.2022.100097
PMCID: PMC8935507
PMID: 35321494
Abstract
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.
TAMM41 is essential in the biosynthesis of cardiolipin, a mitochondrial-specific phospholipid. We identified segregating TAMM41 gene variants in three independent subjects with neuromuscular involvement characterized by mitochondrial oxidative phosphorylation (OXPHOS) defects and decreased cardiolipin levels in muscle. This report highlights the importance of lipid homeostasis for normal mitochondrial function.
Details
- Title: Subtitle
- Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease
- Creators
- Kyle Thompson - Wellcome Centre for Mitochondrial ResearchLucas Bianchi - Délégation Paris 5Francesca Rastelli - Wellcome Centre for Mitochondrial ResearchFlorence Piron-Prunier - Université Paris-SaclaySophie Ayciriex - Université Claude Bernard Lyon 1Claude Besmond - Délégation Paris 5Laurence Hubert - Délégation Paris 5Magalie Barth - Centre Hospitalier Universitaire d'AngersInês A. Barbosa - King's College LondonCharu Deshpande - Guy's and St Thomas' NHS Foundation TrustManali Chitre - Cambridge University Hospitals NHS Foundation TrustSarju G. Mehta - Cambridge University Hospitals NHS Foundation TrustEric J.M. Wever - Netherlands Metabolomics CentrePascale Marcorelles - Department of Pathology, EA4586 LIEN Université de Brest, CHRU Brest, 29609 Brest, FranceSandra Donkervoort - National Institute of Neurological Disorders and StrokeDimah Saade - National Institute of Neurological Disorders and StrokeCarsten G. Bönnemann - National Institute of Neurological Disorders and StrokeKatherine R. Chao - Broad InstituteChunyu Cai - The University of Texas Southwestern Medical CenterSusan T. Iannaccone - The University of Texas Southwestern Medical CenterAndrew F. Dean - Cambridge University Hospitals NHS Foundation TrustRobert McFarland - Newcastle UniversityFrédéric M. Vaz - University of AmsterdamAgnès Delahodde - Université Paris-Saclay, CEA, CNRS, Institute for Integrative Biology of the Cell (I2BC), 91198 Gif-sur-Yvette, FranceRobert W. Taylor - Newcastle UniversityAgnès Rötig - Inserm
- Resource Type
- Journal article
- Publication Details
- HGG advances, Vol.3(2), pp.100097-100097
- DOI
- 10.1016/j.xhgg.2022.100097
- PMID
- 35321494
- PMCID
- PMC8935507
- NLM abbreviation
- HGG Adv
- ISSN
- 2666-2477
- eISSN
- 2666-2477
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 04/14/2022
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Neurology (Pediatrics)
- Record Identifier
- 9984353935202771
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