title: Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness.
abstract: OBJECTIVE
  To identify the cause of a so-far unreported phenotype of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD).
  
  
  METHODS
  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.
  
  
  RESULTS
  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. PTRH2 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.
  
  
  CONCLUSIONS
  We report a novel disease phenotype, show that the genetic cause is a homozygous mutation in the PTRH2 gene, and demonstrate functional effects in mouse and human tissues. Mutations in PTRH2 should be considered in patients with undiagnosed multisystem neurologic, endocrine, and pancreatic disease.
authors.affiliation: Max Planck Institute for Molecular Genetics Berlin, Germany.
authors.forename: Hao
authors.initials: H
authors.lastname: Hu
authors.affiliation: The University of Hawaii Cancer Center Honolulu, Hawaii.
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Matter
authors.affiliation: Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin Berlin, Germany ; Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors.forename: Lina
authors.initials: L
authors.lastname: Issa-Jahns
authors.affiliation: The University of Hawaii Cancer Center Honolulu, Hawaii.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Jijiwa
authors.affiliation: Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin Berlin, Germany ; Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Kraemer
authors.affiliation: Max Planck Institute for Molecular Genetics Berlin, Germany.
authors.forename: Luciana
authors.initials: L
authors.lastname: Musante
authors.affiliation: The University of Hawaii Cancer Center Honolulu, Hawaii.
authors.forename: Michelle
authors.initials: M
authors.lastname: de la Vega
authors.affiliation: Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Ninnemann
authors.affiliation: Department of Human Genetics, University of Würzburg Würzburg, Germany.
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.affiliation: Department of Human Genetics, University of Würzburg Würzburg, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Damatova
authors.affiliation: Department of Human Genetics, University of Würzburg Würzburg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Eirich
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Sifringer
authors.affiliation: Institute of Biochemistry and Cluster of Excellence Neurocure, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schrötter
authors.affiliation: Institute of Biochemistry and Cluster of Excellence Neurocure, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors.forename: Britta J
authors.initials: BJ
authors.lastname: Eickholt
authors.affiliation: Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center Nijmegen, The Netherlands.
authors.forename: Lambert
authors.initials: L
authors.lastname: van den Heuvel
authors.affiliation: The University of Hawaii Cancer Center Honolulu, Hawaii.
authors.forename: Chanel
authors.initials: C
authors.lastname: Casamina
authors.affiliation: Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors.forename: Gisela
authors.initials: G
authors.lastname: Stoltenburg-Didinger
authors.affiliation: Max Planck Institute for Molecular Genetics Berlin, Germany.
authors.forename: Hans-Hilger
authors.initials: HH
authors.lastname: Ropers
authors.affiliation: Max Planck Institute for Molecular Genetics Berlin, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Wienker
authors.affiliation: Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Hübner
authors.affiliation: Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin Berlin, Germany ; Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin Berlin, Germany.
authors.forename: Angela M
authors.initials: AM
authors.lastname: Kaindl