TY - JOUR
T1 - Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease
AU - Thompson, Kyle
AU - Bianchi, Lucas
AU - Rastelli, Francesca
AU - Piron-Prunier, Florence
AU - Ayciriex, Sophie
AU - Besmond, Claude
AU - Hubert, Laurence
AU - Barth, Magalie
AU - Barbosa, Inês A.
AU - Deshpande, Charu
AU - Chitre, Manali
AU - Mehta, Sarju G.
AU - Wever, Eric J.M.
AU - Marcorelles, Pascale
AU - Donkervoort, Sandra
AU - Saade, Dimah
AU - Bönnemann, Carsten G.
AU - Chao, Katherine R.
AU - Cai, Chunyu
AU - Iannaccone, Susan T.
AU - Dean, Andrew F.
AU - McFarland, Robert
AU - Vaz, Frédéric M.
AU - Delahodde, Agnès
AU - Taylor, Robert W.
AU - Rötig, Agnès
N1 - Publisher Copyright:
© 2022 The Authors
PY - 2022/4/14
Y1 - 2022/4/14
N2 - 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.
AB - 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.
KW - OXPHOS defect
KW - WES/WGS
KW - cardiolipin
KW - mitochondria
KW - mitochondrial disease
KW - mitochondrial phospholipid
UR - http://www.scopus.com/inward/record.url?scp=85126594050&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85126594050&partnerID=8YFLogxK
U2 - 10.1016/j.xhgg.2022.100097
DO - 10.1016/j.xhgg.2022.100097
M3 - Article
C2 - 35321494
AN - SCOPUS:85126594050
SN - 2666-2477
VL - 3
JO - Human Genetics and Genomics Advances
JF - Human Genetics and Genomics Advances
IS - 2
M1 - 100097
ER -