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

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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 .

Title: Recurrent De Novo Dominant Mutations in SLC2SA4 Cause Severe Early-Onset Mitochondrial Disease and Loss of Mitochondrial DNA Copy Number
Author: Thompson, Kyle; Majd, Homa; Dallabona, Christina; Reinson, Karit; King, Martin S.; Alston, Charlotte L.; He, Langping; Lodi, Tiziana; Jones, Simon A.; Fattal-Valevski, Aviva; Fraenkel, Nitay D.; Saada, Ann; Haham, Alon; Isohanni, Pirjo; Vara, Roshni; Barbosa, Ines A.; Simpson, Michael A.; Deshpande, Charu; Puusepp, Sanna; Bonnen, Penelope E.; Rodenburg, Richard J.; Suomalainen, Anu; Ounap, Katrin; Elpeleg, Orly; Ferrero, Ileana; McFarland, Robert; Kunji, Edmund R. S.; Taylor, Robert W.
Contributor organization: Research Programme for Molecular Neurology
Research Programs Unit
Anu Wartiovaara / Principal Investigator
Children's Hospital
University of Helsinki
Lastenneurologian yksikkö
Department of Neurosciences
HUS Children and Adolescents
Date: 2016-10-06
Language: eng
Number of pages: 17
Belongs to series: American Journal of Human Genetics
ISSN: 0002-9297
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.
3111 Biomedicine
3123 Gynaecology and paediatrics
3112 Neurosciences
3124 Neurology and psychiatry
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion

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