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

Hu, H., Matter, M. L., Issa-Jahns, L., Jijiwa, M., Kraemer, N., Musante, L., et al. (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), 1024-1035. doi:10.1002/acn3.149.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-C2D8-9 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-0025-C2D9-7
Genre: Journal Article

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 Creators:
Hu, H.1, Author              
Matter, M. L., Author
Issa-Jahns, L., Author
Jijiwa, M., Author
Kraemer, N., Author
Musante, L.2, Author              
de la Vega, M., Author
Ninnemann, O., Author
Schindler, D., Author
Damatova, N., Author
Eirich, K., Author
Sifringer, M., Author
Schrotter, S., Author
Eickholt, B. J., Author
van den Heuvel, L., Author
Casamina, C., Author
Stoltenburg-Didinger, G., Author
Ropers, H. H.1, Author              
Wienker, T. F.3, Author              
Hübner, C., Author
Kaindl, A. M., Author more..
Affiliations:
1Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433549              
2Familial Cognitive Disorders (Luciana Musante), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479644              
3Clinical Genetics (Thomas F. Wienker), Dept. of Human Molecular Genetics (Head: Hans-Hilger Ropers), Max Planck Institute for Molecular Genetics, Max Planck Society, 1479643              

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 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.

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Language(s): eng - English
 Dates: 2014-12-032014-12
 Publication Status: Published in print
 Pages: -
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 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1002/acn3.149
ISSN: 2328-9503 (Electronic)
 Degree: -

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Title: Annals of Clinical and Translational Neurology
Source Genre: Journal
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Publ. Info: American Neurological Association
Pages: - Volume / Issue: 1 (12) Sequence Number: - Start / End Page: 1024 - 1035 Identifier: -