Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease
Kyle Thompson
(1)
,
Lucas Bianchi
(2)
,
Francesca Rastelli
(1)
,
Florence Piron-Prunier
(3)
,
Sophie Ayciriex
(4)
,
Claude Besmond
(2)
,
Laurence Hubert
(2)
,
Magalie Barth
(5)
,
Inês Barbosa
(6)
,
Charu Deshpande
(7)
,
Manali Chitre
(8)
,
Sarju Mehta
(8)
,
Eric J.M. Wever
(9, 10, 11)
,
Pascale Marcorelles
(12, 13)
,
Sandra Donkervoort
(14)
,
Dimah Saade
(14)
,
Carsten Bönnemann
(14)
,
Katherine Chao
(15)
,
Chunyu Cai
(16)
,
Susan Iannaccone
(16)
,
Andrew Dean
(8)
,
Robert Mcfarland
(1, 17)
,
Frédéric Vaz
(9, 11)
,
Agnès Delahodde
(3)
,
Robert Taylor
(1, 17)
,
Agnès Rötig
(2)
1
Newcastle University [Newcastle]
2 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
3 I2BC - Institut de Biologie Intégrative de la Cellule
4 ISA - Institut des Sciences Analytiques
5 CHU Angers - Centre Hospitalier Universitaire d'Angers
6 King‘s College London
7 Guy's and St Thomas NHS Foundation Trust [London]
8 CUH - Cambridge University Hospitals - NHS
9 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
10 Amsterdam Public Health Research Institute [The Netherlands]
11 Amsterdam UMC - Amsterdam University Medical Center
12 LIEN - Laboratoire sur les interactions Epithéliums Neurones
13 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
14 NINDS - National Institute of Neurological Disorders and Stroke [Bethesda]
15 BROAD INSTITUTE - Broad Institute of MIT and Harvard
16 University of Texas Southwestern Medical Center [Dallas]
17 Newcastle Upon Tyne Hospitals NHS Foundation Trust
2 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
3 I2BC - Institut de Biologie Intégrative de la Cellule
4 ISA - Institut des Sciences Analytiques
5 CHU Angers - Centre Hospitalier Universitaire d'Angers
6 King‘s College London
7 Guy's and St Thomas NHS Foundation Trust [London]
8 CUH - Cambridge University Hospitals - NHS
9 UvA - University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
10 Amsterdam Public Health Research Institute [The Netherlands]
11 Amsterdam UMC - Amsterdam University Medical Center
12 LIEN - Laboratoire sur les interactions Epithéliums Neurones
13 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
14 NINDS - National Institute of Neurological Disorders and Stroke [Bethesda]
15 BROAD INSTITUTE - Broad Institute of MIT and Harvard
16 University of Texas Southwestern Medical Center [Dallas]
17 Newcastle Upon Tyne Hospitals NHS Foundation Trust
Florence Piron-Prunier
- Fonction : Auteur
- PersonId : 796865
- ORCID : 0000-0003-2652-5123
Sophie Ayciriex
- Fonction : Auteur
- PersonId : 1150735
- IdHAL : sophie-ayciriex
- ORCID : 0000-0003-4813-5900
- IdRef : 149714882
Sandra Donkervoort
- Fonction : Auteur
- PersonId : 786623
- ORCID : 0000-0001-6399-1444
Katherine Chao
- Fonction : Auteur
- PersonId : 797654
- ORCID : 0000-0003-2897-2410
Résumé
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.
Format du dépôt | Fichier |
---|---|
Type de dépôt | Article dans une revue |
Titre |
en
Biallelic variants in TAMM41 are associated with low muscle cardiolipin levels, leading to neonatal mitochondrial disease
|
Résumé |
en
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.
|
Auteur(s) |
Kyle Thompson
1
, Lucas Bianchi
2
, Francesca Rastelli
1
, Florence Piron-Prunier
3
, Sophie Ayciriex
4
, Claude Besmond
2
, Laurence Hubert
2
, Magalie Barth
5
, Inês Barbosa
6
, Charu Deshpande
7
, Manali Chitre
8
, Sarju Mehta
8
, Eric J.M. Wever
9, 10, 11
, Pascale Marcorelles
12, 13
, Sandra Donkervoort
14
, Dimah Saade
14
, Carsten Bönnemann
14
, Katherine Chao
15
, Chunyu Cai
16
, Susan Iannaccone
16
, Andrew Dean
8
, Robert Mcfarland
1, 17
, Frédéric Vaz
9, 11
, Agnès Delahodde
3
, Robert Taylor
1, 17
, Agnès Rötig
2
1
Newcastle University [Newcastle]
( 252912 )
- Newcastle upon Tyne NE1 7RU
- Royaume-Uni
2
Imagine - U1163 -
Imagine - Institut des maladies génétiques (IHU)
( 1004662 )
- IHU Imagine,
156 rue de Vaugirard, 75015 PARIS
et
24 Boulevard du Montparnasse, 75015 Paris
- France
3
I2BC -
Institut de Biologie Intégrative de la Cellule
( 414518 )
- Bâtiment 21, 1 avenue de la Terrasse, 91198 Gif/Yvette cedex
- France
4
ISA -
Institut des Sciences Analytiques
( 136798 )
- 5 rue de la Doua, 69100 Villeurbanne
- France
5
CHU Angers -
Centre Hospitalier Universitaire d'Angers
( 151939 )
- 4 rue Larrey - 49933 Angers cedex 9
- France
6
King‘s College London
( 327716 )
- Strand Campus, London WC2R 2LS
- Royaume-Uni
7
Guy's and St Thomas NHS Foundation Trust [London]
( 1055688 )
- Royaume-Uni
8
CUH -
Cambridge University Hospitals - NHS
( 241649 )
- Foundation Trust Cambridge Biomedical Campus Hills Road Cambridge CB2 0QQ
- Royaume-Uni
9
UvA -
University of Amsterdam [Amsterdam] = Universiteit van Amsterdam
( 120654 )
- Spui 21 1012 WX Amsterdam
- Pays-Bas
10
Amsterdam Public Health Research Institute [The Netherlands]
( 559767 )
- Pays-Bas
11
Amsterdam UMC - Amsterdam University Medical Center
( 565705 )
- Amsterdam
- Pays-Bas
12
LIEN -
Laboratoire sur les interactions Epithéliums Neurones
( 523317 )
- UFR Médecine, 22 avenue Camille Desmoulins, 29200 Brest
- France
13
CHRU Brest -
Centre Hospitalier Régional Universitaire de Brest
( 356603 )
- France
14
NINDS -
National Institute of Neurological Disorders and Stroke [Bethesda]
( 211879 )
- 35 Convent Drive, Bethesda, MD 20892-3701
- États-Unis
15
BROAD INSTITUTE -
Broad Institute of MIT and Harvard
( 38338 )
- Cambridge, MA 02142
- États-Unis
16
University of Texas Southwestern Medical Center [Dallas]
( 142536 )
- 5323 Harry Hines Boulevard Dallas, Texas, 75390
- États-Unis
17
Newcastle Upon Tyne Hospitals NHS Foundation Trust
( 342760 )
- Queen Victoria Road, Newcastle upon Tyne, NE1 4LP
- Royaume-Uni
|
Langue du document |
Anglais
|
Nom de la revue |
|
Volume |
3
|
Numéro |
2
|
Page/Identifiant |
100097
|
Date de publication |
2022-04
|
Audience |
Internationale
|
Vulgarisation |
Non
|
Comité de lecture |
Oui
|
URL éditeur |
https://www.sciencedirect.com/science/article/pii/S2666247722000136?via%3Dihub
|
Domaine(s) |
|
Projet(s) ANR |
|
Mots-clés |
en
OXPHOS defect, WES/WGS, cardiolipin, mitochondria, mitochondrial disease, mitochondrial phospholipid
|
DOI | 10.1016/j.xhgg.2022.100097 |
Pubmed Id | 35321494 |
PubMed Central | PMC8935507 |
Origine :
Fichiers produits par l'(les) auteur(s)
Licence :
Paternité - Pas de modifications
- CC BY 4.0
Licence :
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