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Hum Mol Genet. 2017 Apr 15;26(8):1458-1464. doi: 10.1093/hmg/ddx048.

PTRH2 gene mutation causes progressive congenital skeletal muscle pathology.

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Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Institute of Cell Biology and Neurobiology.
Department of Pediatric Neurology, Charité -Universitätsmedizin, 13353 Berlin, Germany.
The University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.


Peptidyl-tRNA hydrolase 2 (PTRH2) regulates integrin-mediated pro-survival and apoptotic signaling. PTRH2 is critical in muscle development and regulates myogenic differentiation. In humans a biallelic mutation in the PTRH2 gene causes infantile-onset multisystem disease with progressive muscle weakness. We report here that the Ptrh2 knockout mouse model recapitulates the progressive congenital muscle pathology observed in patients. Ptrh2 null mice demonstrate multiple degenerating and regenerating muscle fibers, increased central nuclei, elevated creatine kinase activity and endomysial fibrosis. This progressive muscle pathology resembles the muscular dystrophy phenotype in humans and mice lacking the α7 integrin. We demonstrate that in normal muscle Ptrh2 associates in a complex with the α7β1 integrin at the sarcolemma and Ptrh2 expression is decreased in α7 integrin null muscle. Furthermore, Ptrh2 expression is altered in skeletal muscle of classical congenital muscular dystrophy mouse models. Ptrh2 levels were up-regulated in dystrophin deficient mdx muscle, which correlates with the elevated levels of the α7β1 integrin observed in mdx muscle and Duchenne muscular dystrophy patients. Similar to the α7 integrin, Ptrh2 expression was decreased in laminin-α2 dyW null gastrocnemius muscle. Our data establishes a PTRH2 mutation as a novel driver of congenital muscle degeneration and identifies a potential novel target to treat muscle myopathies.

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