{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T09:01:01Z","timestamp":1790413261135,"version":"4.1.0"},"reference-count":27,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2016,10,12]],"date-time":"2016-10-12T00:00:00Z","timestamp":1476230400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israel Science Foundation","doi-asserted-by":"publisher","award":["ISF\u20101507\/13"],"award-info":[{"award-number":["ISF\u20101507\/13"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:p>Mitochondrial encephalopathies are a heterogeneous group of disorders that, usually carry grave prognosis. Recently a homozygous mutation, <jats:styled-content style=\"fixed-case\">Gly372Ser<\/jats:styled-content>, in the <jats:italic><jats:styled-content style=\"fixed-case\">TIMM50<\/jats:styled-content><\/jats:italic> gene, was reported in an abstract form, in three sibs who suffered from intractable epilepsy and developmental delay accompanied by 3\u2010methylglutaconic aciduria.<\/jats:p><jats:p>We now report on four patients from two unrelated families who presented with severe intellectual disability and seizure disorder, accompanied by slightly elevated lactate level, 3\u2010methylglutaconic aciduria and variable deficiency of mitochondrial complex V. Using exome analysis we identified two homozygous missense mutations, <jats:styled-content style=\"fixed-case\">Arg217Trp<\/jats:styled-content> and <jats:styled-content style=\"fixed-case\">Thr252Met<\/jats:styled-content>, in the <jats:italic><jats:styled-content style=\"fixed-case\">TIMM50<\/jats:styled-content><\/jats:italic> gene. The  <jats:styled-content style=\"fixed-case\">TIMM50<\/jats:styled-content> protein is a subunit of <jats:styled-content style=\"fixed-case\">TIM23<\/jats:styled-content> complex, the mitochondrial import machinery. It serves as the major receptor in the intermembrane space, binding to  proteins which cross the mitochondrial inner membrane on their way to the matrix. The mutations, which  affected evolutionary conserved residues and segregated with the disease in the families, were neither present in large cohorts of control exome analyses nor in our ethnic specific exome cohort. Given the phenotypic similarity, we conclude that missense mutations in <jats:italic><jats:styled-content style=\"fixed-case\">TIMM50<\/jats:styled-content><\/jats:italic> are likely manifesting by severe intellectual disability and epilepsy accompanied by 3\u2010methylglutaconic aciduria and variable mitochondrial complex V deficiency. 3\u2010methylglutaconic aciduria is emerging as an important biomarker for mitochondrial dysfunction, in particular for mitochondrial membrane defects.<\/jats:p>","DOI":"10.1111\/cge.12855","type":"journal-article","created":{"date-parts":[[2016,8,30]],"date-time":"2016-08-30T08:39:32Z","timestamp":1472546372000},"page":"690-696","source":"Crossref","is-referenced-by-count":42,"title":["Mitochondrial epileptic encephalopathy, 3\u2010methylglutaconic aciduria and variable complex V deficiency associated with <i><scp>TIMM50<\/scp><\/i> mutations"],"prefix":"10.1111","volume":"91","author":[{"given":"M.A.","family":"Shahrour","sequence":"first","affiliation":[{"name":"Department of Pediatrics Al\u2010Makassed Islamic Hospital  Jerusalem Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"O.","family":"Staretz\u2010Chacham","sequence":"additional","affiliation":[{"name":"Metabolic Disease Unit Soroka Medical Center, Faculty of Health Sciences, Ben\u2010Gurion University of the Negev  Beer Sheba Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D.","family":"Dayan","sequence":"additional","affiliation":[{"name":"Department of Biochemistry &amp; 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