Display options
Cite
Hu H, Matter ML, Issa-Jahns L, et al. Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness. Ann Clin Transl Neurol. 2014;1(12):1024-35doi: 10.1002/acn3.149.
Hu, H., Matter, M. L., Issa-Jahns, L., Jijiwa, M., Kraemer, N., Musante, L., de la Vega, M., Ninnemann, O., Schindler, D., Damatova, N., Eirich, K., Sifringer, M., Schrötter, S., Eickholt, B. J., van den Heuvel, L., Casamina, C., Stoltenburg-Didinger, G., Ropers, H. H., Wienker, T. F., Hübner, C., & Kaindl, A. M. (2014). Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness. Annals of clinical and translational neurology, 1(12), 1024-35. https://doi.org/10.1002/acn3.149
Hu, Hao, et al. "Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness." Annals of clinical and translational neurology vol. 1,12 (2014): 1024-35. doi: https://doi.org/10.1002/acn3.149
Hu H, Matter ML, Issa-Jahns L, Jijiwa M, Kraemer N, Musante L, de la Vega M, Ninnemann O, Schindler D, Damatova N, Eirich K, Sifringer M, Schrötter S, Eickholt BJ, van den Heuvel L, Casamina C, Stoltenburg-Didinger G, Ropers HH, Wienker TF, Hübner C, Kaindl AM. Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness. Ann Clin Transl Neurol. 2014 Dec;1(12):1024-35. doi: 10.1002/acn3.149. Epub 2014 Dec 03. PMID: 25574476; PMCID: PMC4284127.
Copy Download .nbib Format: NLM
Share it on

Ann Clin Transl Neurol. 2014 Dec;1(12):1024-35. doi: 10.1002/acn3.149. Epub 2014 Dec 03.

Mutations in PTRH2 cause novel infantile-onset multisystem disease with intellectual disability, microcephaly, progressive ataxia, and muscle weakness.

Annals of clinical and translational neurology

Hao Hu, Michelle L Matter, Lina Issa-Jahns, Mayumi Jijiwa, Nadine Kraemer, Luciana Musante, Michelle de la Vega, Olaf Ninnemann, Detlev Schindler, Natalia Damatova, Katharina Eirich, Marco Sifringer, Sandra Schrötter, Britta J Eickholt, Lambert van den Heuvel, Chanel Casamina, Gisela Stoltenburg-Didinger, Hans-Hilger Ropers, Thomas F Wienker, Christoph Hübner, Angela M Kaindl

Affiliations

  1. Max Planck Institute for Molecular Genetics Berlin, Germany.
  2. The University of Hawaii Cancer Center Honolulu, Hawaii.
  3. Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin Berlin, Germany ; Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin Berlin, Germany.
  4. Institute of Cell Biology and Neurobiology, Charité - Universitätsmedizin Berlin Berlin, Germany.
  5. Department of Human Genetics, University of Würzburg Würzburg, Germany.
  6. Department of Anesthesiology and Intensive Care Medicine, Charité - Universitätsmedizin Berlin Berlin, Germany.
  7. Institute of Biochemistry and Cluster of Excellence Neurocure, Charité - Universitätsmedizin Berlin Berlin, Germany.
  8. Nijmegen Center for Mitochondrial Disorders, Radboud University Medical Center Nijmegen, The Netherlands.
  9. Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin Berlin, Germany.

PMID: 25574476 PMCID: PMC4284127 DOI: 10.1002/acn3.149

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.

INTERPRETATION: 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.

References

  1. Oncogene. 2003 May 22;22(21):3307-18 - PubMed
  2. Helv Paediatr Acta Suppl. 1989 Jun;52:1-125 - PubMed
  3. Nat Cell Biol. 2007 Sep;9(9):1081-8 - PubMed
  4. J Biol Chem. 2008 Oct 17;283(42):28029-37 - PubMed
  5. Neurol Res. 2012 Sep;34(7):664-8 - PubMed
  6. Am J Hum Genet. 2008 Nov;83(5):610-5 - PubMed
  7. Clin Chem. 2006 May;52(5):860-71 - PubMed
  8. Cell. 2004 Mar 5;116(5):751-62 - PubMed
  9. Cereb Cortex. 2013 Sep;23(9):2245-60 - PubMed
  10. Proc Natl Acad Sci U S A. 2008 Feb 5;105(5):1528-32 - PubMed
  11. J Biol Chem. 2001 Nov 30;276(48):45380-6 - PubMed
  12. Genesis. 2000 Feb;26(2):113-5 - PubMed
  13. Nature. 2011 Sep 21;478(7367):57-63 - PubMed
  14. Klin Padiatr. 1994 Jan-Feb;206(1):12-7 - PubMed
  15. J Biol Chem. 2011 Apr 22;286(16):14713-23 - PubMed
  16. BMC Neurosci. 2006 Sep 20;7:64 - PubMed
  17. Am J Hum Genet. 2009 Dec;85(6):897-902 - PubMed
  18. Hum Genet. 1986 Aug;73(4):320-6 - PubMed
  19. J Biol Chem. 2004 Feb 27;279(9):8111-5 - PubMed
  20. Cell. 2002 Jul 26;110(2):163-75 - PubMed
  21. J Neurosci. 2008 Apr 9;28(15):3911-9 - PubMed
  22. Hum Mutat. 2014 Dec;35(12):1427-35 - PubMed
  23. J Biol Chem. 1976 Jun 10;251(11):3392-8 - PubMed

Publication Types

Grant support