Mutations in PTRH2 cause novel infantile‐onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness. (3rd December 2014)

• Record Type: Journal Article
• Authors: Hu, Hao; Matter, Michelle L.; Issa‐Jahns, Lina; Jijiwa, Mayumi; Kraemer, Nadine; Musante, Luciana; de la Vega, Michelle; Ninnemann, Olaf; Schindler, Detlev; Damatova, Natalia; Eirich, Katharina; Sifringer, Marco; Schrötter, Sandra; Eickholt, Britta J.; van den Heuvel, Lambert; Casamina, Chanel; Stoltenburg‐Didinger, Gisela; Ropers, Hans‐Hilger; Wienker, Thomas F.; Hübner, Christoph; Kaindl, Angela M.
• Is Part Of: Annals of clinical and translational neurology. Volume 1:Number 12(2014)
• Page Start: 1024
• Page End: 1035
• Publication Date: 2014-12-03
• Subjects: Nervous system -- Diseases -- Periodicals; Neurology -- Periodicals; 616.8005
• DOI: 10.1002/acn3.149
• Languages: English
• ISSNs: 2328-9503

Abstract

<abstract abstract-type="main" id="acn3149-abs-0001"> <title>Abstract</title> <sec id="acn3149-sec-0001" sec-type="section"> <title>Objective</title> <p>To identify the cause of a so‐far unreported phenotype of infantile‐onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD).</p> </sec> <sec id="acn3149-sec-0002" sec-type="section"> <title>Methods</title> <p>We characterized a consanguineous family of Yazidian‐Turkish 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‐exome 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‐type and mutant mice and in patient and control fibroblasts.</p> </sec> <sec id="acn3149-sec-0003" sec-type="section"> <title>Results</title> <p>In a consanguineous family with two individuals with IMNEPD, we identified a homozygous frameshift mutation in the previously not disease‐associated peptidyl‐tRNA hydrolase 2 (PTRH2) gene. <italic>PTRH2</italic> encodes a primarily mitochondrial protein involved in integrin‐mediated 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.</p> </sec> <sec id="acn3149-sec-0004" sec-type="section"> <title>Interpretation</title> <p>We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the <italic>PTRH2</italic> gene, and demonstrate functional effects in mouse and human tissues. Mutations in <italic>PTRH2</italic> should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease.</p> </sec> </abstract>