000079519 001__ 79519
000079519 005__ 20191127155459.0
000079519 0247_ $$2doi$$a10.1093/hmg/ddy305
000079519 0248_ $$2sideral$$a109002
000079519 037__ $$aART-2018-109002
000079519 041__ $$aeng
000079519 100__ $$aPacheu-Grau, David
000079519 245__ $$aMutations of the mitochondrial carrier translocase channel subunit TIM22 cause early-onset mitochondrial myopathy
000079519 260__ $$c2018
000079519 5060_ $$aAccess copy available to the general public$$fUnrestricted
000079519 5203_ $$aProtein import into mitochondria is facilitated by translocases within the outer and the inner mitochondrial membranes that are dedicated to a highly specific subset of client proteins. The mitochondrial carrier translocase (TIM22 complex) inserts multispanning proteins, such as mitochondrial metabolite carriers and translocase subunits (TIM23, TIM17A/B and TIM22), into the inner mitochondrial membrane. Both types of substrates are essential for mitochondrial metabolic function and biogenesis. Here, we report on a subject, diagnosed at 1.5 years, with a neuromuscular presentation, comprising hypotonia, gastroesophageal reflux disease and persistently elevated serum and Cerebrospinal fluid lactate (CSF). Patient fibroblasts displayed reduced oxidative capacity and altered mitochondrial morphology. Using trans-mitochondrial cybrid cell lines, we excluded a candidate variant in mitochondrial DNA as causative of these effects. Whole-exome sequencing identified compound heterozygous variants in the TIM22 gene (NM_013337), resulting in premature truncation in one allele (p.Tyr25Ter) and a point mutation in a conserved residue (p.Val33Leu), within the intermembrane space region, of the TIM22 protein in the second allele. Although mRNA transcripts of TIM22 were elevated, biochemical analyses revealed lower levels of TIM22 protein and an even greater deficiency of TIM22 complex formation. In agreement with a defect in carrier translocase function, carrier protein amounts in the inner membrane were found to be reduced. This is the first report of pathogenic variants in the TIM22 pore-forming subunit of the carrier translocase affecting the biogenesis of inner mitochondrial membrane proteins critical for metabolite exchange.
000079519 536__ $$9info:eu-repo/grantAgreement/ES/ISCIII/PI17-00166$$9info:eu-repo/grantAgreement/ES/ISCIII/PI17-00021
000079519 540__ $$9info:eu-repo/semantics/openAccess$$aby-nc$$uhttp://creativecommons.org/licenses/by-nc/3.0/es/
000079519 590__ $$a4.544$$b2018
000079519 591__ $$aGENETICS & HEREDITY$$b32 / 174 = 0.184$$c2018$$dQ1$$eT1
000079519 591__ $$aBIOCHEMISTRY & MOLECULAR BIOLOGY$$b62 / 294 = 0.211$$c2018$$dQ1$$eT1
000079519 592__ $$a3.097$$b2018
000079519 593__ $$aGenetics$$c2018$$dQ1
000079519 593__ $$aMolecular Biology$$c2018$$dQ1
000079519 593__ $$aMedicine (miscellaneous)$$c2018$$dQ1
000079519 593__ $$aGenetics (clinical)$$c2018$$dQ1
000079519 655_4 $$ainfo:eu-repo/semantics/article$$vinfo:eu-repo/semantics/publishedVersion
000079519 700__ $$aCallegari, Sylvie
000079519 700__ $$0(orcid)0000-0001-5964-6138$$aEmperador, Sonia$$uUniversidad de Zaragoza
000079519 700__ $$aThompson, Kyle
000079519 700__ $$aAich, Abhishek
000079519 700__ $$aTopol, Sarah E.
000079519 700__ $$aSpencer, Emily G.
000079519 700__ $$aMcFarland, Robert
000079519 700__ $$0(orcid)0000-0002-0269-7337$$aRuiz-Pesini, Eduardo$$uUniversidad de Zaragoza
000079519 700__ $$aTorkamani, Ali
000079519 700__ $$aTaylor, Robert W.
000079519 700__ $$0(orcid)0000-0003-1770-6299$$aMontoya, Julo$$uUniversidad de Zaragoza
000079519 700__ $$aRehling, Peter
000079519 7102_ $$11003$$2443$$aUniversidad de Zaragoza$$bDpto. Anatom.Histolog.Humanas$$cArea Histología
000079519 7102_ $$11002$$2060$$aUniversidad de Zaragoza$$bDpto. Bioq.Biolog.Mol. Celular$$cÁrea Bioquímica y Biolog.Mole.
000079519 773__ $$g27, 23 (2018), 4135-4144$$pHum. mol. genet.$$tHUMAN MOLECULAR GENETICS$$x0964-6906
000079519 8564_ $$s7397262$$uhttps://zaguan.unizar.es/record/79519/files/texto_completo.pdf$$yVersión publicada
000079519 8564_ $$s94409$$uhttps://zaguan.unizar.es/record/79519/files/texto_completo.jpg?subformat=icon$$xicon$$yVersión publicada
000079519 909CO $$ooai:zaguan.unizar.es:79519$$particulos$$pdriver
000079519 951__ $$a2019-11-27-15:49:17
000079519 980__ $$aARTICLE