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Perry Fund","award":["20061479"],"award-info":[{"award-number":["20061479"]}]},{"DOI":"10.13039\/100010121","name":"Sonnenfeld Stiftung","doi-asserted-by":"crossref","award":["-"],"award-info":[{"award-number":["-"]}],"id":[{"id":"10.13039\/100010121","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Ann Clin Transl Neurol"],"published-print":{"date-parts":[[2014,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Objective<\/jats:title><jats:p>To identify the cause of a so\u2010far unreported phenotype of infantile\u2010onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We characterized a consanguineous family of Yazidian\u2010Turkish descent with IMNEPD. The two affected children suffer from intellectual disability, postnatal microcephaly, growth retardation, progressive ataxia, distal muscle weakness, peripheral demyelinating sensorimotor neuropathy, sensorineural deafness, exocrine pancreas insufficiency, hypothyroidism, and show signs of liver fibrosis. We performed whole\u2010exome sequencing followed by bioinformatic analysis and Sanger sequencing on affected and unaffected family members. The effect of mutations in the candidate gene was studied in wild\u2010type and mutant mice and in patient and control fibroblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease\u2010associated peptidyl\u2010tRNA hydrolase 2 (PTRH2) gene. <jats:italic>PTRH2<\/jats:italic> encodes a primarily mitochondrial protein involved in integrin\u2010mediated cell survival and apoptosis signaling. We show that PTRH2 is highly expressed in the developing brain and is a key determinant in maintaining cell survival during human tissue development. Moreover, we link PTRH2 to the mTOR pathway and thus the control of cell size. The pathology suggested by the human phenotype and neuroimaging studies is supported by analysis of mutant mice and patient fibroblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the <jats:italic>PTRH2<\/jats:italic> gene, and demonstrate functional effects in mouse and human tissues. Mutations in <jats:italic>PTRH2<\/jats:italic> should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease.<\/jats:p><\/jats:sec>","DOI":"10.1002\/acn3.149","type":"journal-article","created":{"date-parts":[[2014,12,3]],"date-time":"2014-12-03T11:27:03Z","timestamp":1417606023000},"page":"1024-1035","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Mutations in <i>PTRH2<\/i> cause novel infantile\u2010onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness"],"prefix":"10.1002","volume":"1","author":[{"given":"Hao","family":"Hu","sequence":"first","affiliation":[{"name":"Max Planck Institute for Molecular Genetics Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle L.","family":"Matter","sequence":"additional","affiliation":[{"name":"The University of Hawaii Cancer Center Honolulu 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