Journal article
Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization
American journal of human genetics, Vol.99(5), pp.1086-1105
11/03/2016
DOI: 10.1016/j.ajhg.2016.09.005
PMCID: PMC5097943
PMID: 27745833
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 pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins (FAD-binding) and catalyze pyridine-nucleotide-dependent (NAD/NADH) reduction of thiol residues in other proteins. Complementation experiments in yeast lacking glutathione reductase glr1 show that human PYROXD1 has reductase activity that is strongly impaired by the disease-associated missense mutations. Immunolocalization studies in human muscle and zebrafish myofibers demonstrate that PYROXD1 localizes to the nucleus and to striated sarcomeric compartments. Zebrafish with ryroxD1 knock-down recapitulate features of PYROXD1 myopathy with sarcomeric disorganization, myofibrillar aggregates, and marked swimming defect. We characterize variants in the oxidoreductase PYROXD1 as a cause of early-onset myopathy with distinctive histopathology and introduce altered redox regulation as a primary cause of congenital muscle disease.
Details
- Title: Subtitle
- Variants in the Oxidoreductase PYROXD1 Cause Early-Onset Myopathy with Internalized Nuclei and Myofibrillar Disorganization
- Creators
- Gina L O'Grady - The University of SydneyHeather A Best - The University of SydneyTamar E Sztal - Monash UniversityVanessa Schartner - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, FranceMyriam Sanjuan-Vazquez - Université de StrasbourgSandra Donkervoort - National Institute of Neurological Disorders and StrokeOsorio Abath Neto - Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), 67400 Illkirch, FranceRoger Bryan Sutton - Texas Tech University Health Sciences CenterBiljana Ilkovski - Children's Hospital at WestmeadNorma Beatriz Romero - Université Paris CitéTanya Stojkovic - Centre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 7503 Paris, FranceJahannaz Dastgir - National Institute of Neurological Disorders and StrokeLeigh B Waddell - Children's Hospital at WestmeadAnne Boland - Centre National de Recherche en Génomique HumaineYing Hu - National Institute of Neurological Disorders and StrokeCaitlin Williams - Monash UniversityAvnika A Ruparelia - Monash UniversityThierry Maisonobe - Centre de Référence de Pathologie Neuromusculaire Paris-Est, Institut de Myologie, GHU La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, 7503 Paris, FranceAnthony J Peduto - The University of SydneyStephen W Reddel - The University of SydneyMonkol Lek - Harvard UniversityTaru Tukiainen - Harvard UniversityBeryl B Cummings - Harvard UniversityHimanshu Joshi - Children's Hospital at WestmeadJuliette Nectoux - Délégation Paris 5Susan Brammah - Concord Repatriation General HospitalJean-François Deleuze - Centre National de Recherche en Génomique HumaineViola Oorschot Ing - Monash UniversityGeorg Ramm - Monash UniversityDidem Ardicli - Boston Children's HospitalKristen J Nowak - Harry Perkins Institute of Medical ResearchBeril Talim - Boston Children's HospitalHaluk Topaloglu - Boston Children's HospitalNigel G Laing - Harry Perkins Institute of Medical ResearchKathryn N North - Children's Hospital at WestmeadDaniel G MacArthur - Harvard UniversitySylvie Friant - Université de StrasbourgNigel F Clarke - The University of SydneyRobert J Bryson-Richardson - Monash UniversityCarsten G Bönnemann - National Institute of Neurological Disorders and StrokeJocelyn Laporte - Université de StrasbourgSandra T Cooper - The University of Sydney
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.99(5), pp.1086-1105
- DOI
- 10.1016/j.ajhg.2016.09.005
- PMID
- 27745833
- PMCID
- PMC5097943
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Grant note
- R01 AR063634 / NIAMS NIH HHS UM1 HG008900 / NHGRI NIH HHS U54 HG003067 / NHGRI NIH HHS
- Language
- English
- Date published
- 11/03/2016
- Academic Unit
- Pathology
- Record Identifier
- 9984277263202771
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