PTRH2 gene mutation causes progressive congenital skeletal muscle pathology.
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.
Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Jinger
J
Doe
Institute of Cell Biology and Neurobiology.|Department of Pediatric Neurology, Charité -Universitätsmedizin, 13353 Berlin, Germany.
Angela M
AM
Kaindl
The University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
Mayumi
M
Jijiwa
The University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
Michelle
M
de la Vega
Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Hao
H
Hu
The University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
Genevieve S
GS
Griffiths
Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Tatiana M
TM
Fontelonga
Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Pamela
P
Barraza
Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Vivian
V
Cruz
Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Pam
P
Van Ry
The University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
Joe W
JW
Ramos
Department of Pharmacology, University of Nevada School of Medicine, Reno, NV 89557, USA.
Dean J
DJ
Burkin
The University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
Michelle L
ML
Matter
D000818:Animals; D002265:Carboxylic Ester Hydrolases / Q000096:biosynthesis / Q000235:genetics*; D016189:Dystrophin / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D016023:Integrins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D018101:Mice, Inbred mdx; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000096:biosynthesis / Q000235:genetics*; D024510:Muscle Development / Q000235:genetics; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000473:pathology; D012508:Sarcolemma / Q000235:genetics / Q000473:pathology
D016189:Dystrophin; D016023:Integrins; D024101:Mitochondrial Proteins; D002265:Carboxylic Ester Hydrolases; C483418:PTH2 protein, human; C527112:Ptrh2 protein, mouse; C082908:integrin alpha7beta1