Recurrent De Novo Dominant Mutations in SLC2SA4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number

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dc.contributor.author Thompson, Kyle
dc.contributor.author Majd, Homa
dc.contributor.author Dallabona, Christina
dc.contributor.author Reinson, Karit
dc.contributor.author King, Martin S.
dc.contributor.author Alston, Charlotte L.
dc.contributor.author He, Langping
dc.contributor.author Lodi, Tiziana
dc.contributor.author Jones, Simon A.
dc.contributor.author Fattal-Valevski, Aviva
dc.contributor.author Fraenkel, Nitay D.
dc.contributor.author Saada, Ann
dc.contributor.author Haham, Alon
dc.contributor.author Isohanni, Pirjo
dc.contributor.author Vara, Roshni
dc.contributor.author Barbosa, Ines A.
dc.contributor.author Simpson, Michael A.
dc.contributor.author Deshpande, Charu
dc.contributor.author Puusepp, Sanna
dc.contributor.author Bonnen, Penelope E.
dc.contributor.author Rodenburg, Richard J.
dc.contributor.author Suomalainen, Anu
dc.contributor.author Ounap, Katrin
dc.contributor.author Elpeleg, Orly
dc.contributor.author Ferrero, Ileana
dc.contributor.author McFarland, Robert
dc.contributor.author Kunji, Edmund R. S.
dc.contributor.author Taylor, Robert W.
dc.date.accessioned 2016-11-11T09:19:03Z
dc.date.available 2016-11-11T09:19:03Z
dc.date.issued 2016-10-06
dc.identifier.citation Thompson , K , Majd , H , Dallabona , C , Reinson , K , King , M S , Alston , C L , He , L , Lodi , T , Jones , S A , Fattal-Valevski , A , Fraenkel , N D , Saada , A , Haham , A , Isohanni , P , Vara , R , Barbosa , I A , Simpson , M A , Deshpande , C , Puusepp , S , Bonnen , P E , Rodenburg , R J , Suomalainen , A , Ounap , K , Elpeleg , O , Ferrero , I , McFarland , R , Kunji , E R S & Taylor , R W 2016 , ' Recurrent De Novo Dominant Mutations in SLC2SA4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number ' , American Journal of Human Genetics , vol. 99 , no. 4 , pp. 860-876 . https://doi.org/10.1016/j.ajhg.2016.08.014
dc.identifier.other PURE: 71305047
dc.identifier.other PURE UUID: 2fb80170-8795-40c7-b215-b645db44beff
dc.identifier.other WOS: 000385333700006
dc.identifier.other Scopus: 84991735971
dc.identifier.uri http://hdl.handle.net/10138/168837
dc.description.abstract Mutations in SLC25A4 encoding the mitochondrial ADP/ATP carrier AAC1 are well-recognized causes of mitochondrial disease. Several heterozygous SLC25A4 mutations cause adult-onset autosomal-dominant progressive external ophthalmoplegia associated with multiple mitochondrial DNA deletions, whereas recessive SLC25A4 mutations cause childhood-onset mitochondrial myopathy and cardiomyopathy. Here, we describe the identification by whole-exome sequencing of seven probands harboring dominant, de novo SLC25A4 mutations. All affected individuals presented at birth, were ventilator dependent and, where tested, revealed severe combined mitochondria' respiratory chain deficiencies associated with a marked loss of mitochondria' DNA copy number in skeletal muscle. Strikingly, an identical c.239G>A (p.Arg80His) mutation was present in four of the seven subjects, and the other three case subjects harbored the same c.703C>G (p.Arg235Gly) mutation. Analysis of skeletal muscle revealed a marked decrease of AAC1 protein levels and loss of respiratory chain complexes containing mitochondria' DNA-encoded subunits. We show that both recombinant AAC1 mutant proteins are severely impaired in ADP/ATP transport, affecting most likely the substrate binding and mechanics of the carrier, respectively. This highly reduced capacity for transport probably affects mitochondria' DNA maintenance and in turn respiration, causing a severe energy crisis. The confirmation of the pathogenicity of these de novo SLC25A4 mutations highlights a third distinct clinical phenotype associated with mutation of this gene and demonstrates that early-onset mitochondria' disease can be caused by recurrent de novo mutations, which has significant implications for the application and analysis of whole-exome sequencing data in mitochondrial disease. en
dc.format.extent 17
dc.language.iso eng
dc.relation.ispartof American Journal of Human Genetics
dc.rights cc_by
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject ADENINE-NUCLEOTIDE TRANSLOCATOR
dc.subject PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA
dc.subject SUBSTRATE-BINDING SITE
dc.subject ADP/ATP CARRIER
dc.subject SACCHAROMYCES-CEREVISIAE
dc.subject TRANSPORT MECHANISM
dc.subject RESPIRATORY-CHAIN
dc.subject ANT1 GENE
dc.subject FUNCTIONAL-CHARACTERIZATION
dc.subject BACTERIAL EXPRESSION
dc.subject 3111 Biomedicine
dc.subject 3123 Gynaecology and paediatrics
dc.subject 3112 Neurosciences
dc.subject 3124 Neurology and psychiatry
dc.title Recurrent De Novo Dominant Mutations in SLC2SA4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number en
dc.type Article
dc.contributor.organization Research Programme for Molecular Neurology
dc.contributor.organization Research Programs Unit
dc.contributor.organization Anu Wartiovaara / Principal Investigator
dc.contributor.organization Clinicum
dc.contributor.organization Children's Hospital
dc.contributor.organization University of Helsinki
dc.contributor.organization Lastenneurologian yksikkö
dc.contributor.organization Department of Neurosciences
dc.contributor.organization HUS Children and Adolescents
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1016/j.ajhg.2016.08.014
dc.relation.issn 0002-9297
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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