Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization

GL O'Grady; HA Best; TE Sztal; V Schartner; M Sanjuan-Vazquez; S Donkervoort; O Abath Neto; RB Sutton; B Ilkovski; NB Romero; T Stojkovic; J Dastgir; LB Waddell; A Boland; Y Hu; C Williams; AA Ruparelia; T Maisonobe; AJ Peduto; SW Reddel; M Lek; T Tukiainen; BB Cummings; H Joshi; J Nectoux; S Brammah; JF Deleuze; VO Ing; G Ramm; D Ardicli; KJ Nowak; B Talim; H Topaloglu; NG Laing; KN North; DG MacArthur; S Friant; NF Clarke; RJ Bryson-Richardson; CG Bönnemann; J Laporte; ST Cooper

Journal article

Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization

GL O'Grady, HA Best, TE Sztal, V Schartner, M Sanjuan-Vazquez, S Donkervoort, O Abath Neto, RB Sutton, B Ilkovski, NB Romero, T Stojkovic, J Dastgir, LB Waddell, A Boland, Y Hu, C Williams, AA Ruparelia, T Maisonobe, AJ Peduto, SW Reddel Show all

American Journal of Human Genetics | CELL PRESS | Published : 2016

DOI: 10.1016/j.ajhg.2016.09.005

Abstract

This study establishes PYROXD1 variants as a cause of early-onset myopathy and uses biospecimens and cell lines, yeast, and zebrafish models to elucidate the fundamental role of PYROXD1 in skeletal muscle. Exome sequencing identified recessive variants in PYROXD1 in nine probands from five families. Affected individuals presented in infancy or childhood with slowly progressive proximal and distal weakness, facial weakness, nasal speech, swallowing difficulties, and normal to moderately elevated creatine kinase. Distinctive histopathology showed abundant internalized nuclei, myofibrillar disorganization, desmin-positive inclusions, and thickened Z-bands. PYROXD1 is a nuclear-cytoplasmic pyrid..

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University of Melbourne Researchers

Avnika Ruparelia Author

Kathryn North Author

Grants

Awarded by Royal Australasian College of Physicians

Funding Acknowledgements

This study was supported by the following funding: The Australian National Health and Medical Research Council (NHMRC) 1080587 (S.T.C., N.F.C., D.G.M., K.N.N., R.B.R., K.J.N., N.G.L.), 1022707 and 1031893 (K.N.N., N.F.C., and N.G.L.), 1048816 (S.T.C.), and 1056285 (G.L.O.), Muscular Dystrophy New South Wales (G.L.O.), Royal Australasian College of Physicians (G.L.O.), Australian Research Council FT100100734 (K.J.N.), National Human Genome Research Institute of the NIH (D.G.M., Medical Sequencing Program grant U54 HG003067 to the Broad Institute principal investigator, Lander), Division of Intramural Research of the National Institutes of Neurological Disorders and Stroke, France Genomique National infrastructure grant Investissements d'Avenir and Agence Nationale pour la Recherche (ANR-10-INBS-09 and ANR-11-BSV1-026), Fondation Maladies Rares "Myocapture" sequencing project, Association Frangaise contre les Myopathies (AFM-15352 and AFM-16551), Muscular Dystrophy Association (MDA-186985), Myotubular Trust and IDEX-Universite de Strasbourg PhD fellowship (M.S.-V), and intramural funds of the NINDS/NIH (C.G.B. and S.D.).