Variants in the oxidoreductase PYROXD1 cause early-onset myopathy with internalized nuclei and myofibrillar disorganization

Gina L O'Grady, Heather A Best, Tamar E Sztal, Vanessa Schartner, Myriam Sanjuan-Vazquez, Sandra Donkervoort, Osorio Abath Neto, Roger Bryan Sutton, Biljana Ilkovski, Norma Beatriz Romero, Tanya Stojkovic, Jahannaz Dastgir, Leigh B Waddell, Anne Boland, Ying Hu, Caitlin Williams, Avnika A Ruparelia, Thierry Maisonobe, Anthony J Peduto, Stephen W Reddel & 22 others Monkol Lek, Taru Tukainen, Beryl B Cummings, Himanshu Joshi, Juliette Nectoux, Susan Brammah, Jean-Francois Deleuze, Viola Oorschot Ing, Georg Ramm, Didem Ardicli, Kristen J Nowak, Beril Talim, Haluk Topaloglu, Nigel G Laing, Kathryn N North, Daniel G MacArthur, Sylvie Friant, Nigel F Clarke, Robert J Bryson-Richardson, Carsten G Bonnemann, Jocelyn Laporte, Sandra T Cooper

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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.
Original languageEnglish
Pages (from-to)1086-1105
Number of pages20
JournalAmerican Journal of Human Genetics
DOIs
Publication statusPublished - 3 Nov 2016

Cite this

O'Grady, Gina L ; Best, Heather A ; Sztal, Tamar E ; Schartner, Vanessa ; Sanjuan-Vazquez, Myriam ; Donkervoort, Sandra ; Neto, Osorio Abath ; Sutton, Roger Bryan ; Ilkovski, Biljana ; Romero, Norma Beatriz ; Stojkovic, Tanya ; Dastgir, Jahannaz ; Waddell, Leigh B ; Boland, Anne ; Hu, Ying ; Williams, Caitlin ; Ruparelia, Avnika A ; Maisonobe, Thierry ; Peduto, Anthony J ; Reddel, Stephen W ; Lek, Monkol ; Tukainen, Taru ; Cummings, Beryl B ; Joshi, Himanshu ; Nectoux, Juliette ; Brammah, Susan ; Deleuze, Jean-Francois ; Ing, Viola Oorschot ; Ramm, Georg ; Ardicli, Didem ; Nowak, Kristen J ; Talim, Beril ; Topaloglu, Haluk ; Laing, Nigel G ; North, Kathryn N ; MacArthur, Daniel G ; Friant, Sylvie ; Clarke, Nigel F ; Bryson-Richardson, Robert J ; Bonnemann, Carsten G ; Laporte, Jocelyn ; Cooper, Sandra T. / Variants in the oxidoreductase PYROXD1 cause early-onset myopathy with internalized nuclei and myofibrillar disorganization. In: American Journal of Human Genetics. 2016 ; pp. 1086-1105.
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title = "Variants in the oxidoreductase PYROXD1 cause early-onset myopathy with internalized nuclei and myofibrillar disorganization",
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.",
author = "O'Grady, {Gina L} and Best, {Heather A} and Sztal, {Tamar E} and Vanessa Schartner and Myriam Sanjuan-Vazquez and Sandra Donkervoort and Neto, {Osorio Abath} and Sutton, {Roger Bryan} and Biljana Ilkovski and Romero, {Norma Beatriz} and Tanya Stojkovic and Jahannaz Dastgir and Waddell, {Leigh B} and Anne Boland and Ying Hu and Caitlin Williams and Ruparelia, {Avnika A} and Thierry Maisonobe and Peduto, {Anthony J} and Reddel, {Stephen W} and Monkol Lek and Taru Tukainen and Cummings, {Beryl B} and Himanshu Joshi and Juliette Nectoux and Susan Brammah and Jean-Francois Deleuze and Ing, {Viola Oorschot} and Georg Ramm and Didem Ardicli and Nowak, {Kristen J} and Beril Talim and Haluk Topaloglu and Laing, {Nigel G} and North, {Kathryn N} and MacArthur, {Daniel G} and Sylvie Friant and Clarke, {Nigel F} and Bryson-Richardson, {Robert J} and Bonnemann, {Carsten G} and Jocelyn Laporte and Cooper, {Sandra T}",
year = "2016",
month = "11",
day = "3",
doi = "10.1016/j.ajhg.2016.09.005",
language = "English",
pages = "1086--1105",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",

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O'Grady, GL, Best, HA, Sztal, TE, Schartner, V, Sanjuan-Vazquez, M, Donkervoort, S, Neto, OA, Sutton, RB, Ilkovski, B, Romero, NB, Stojkovic, T, Dastgir, J, Waddell, LB, Boland, A, Hu, Y, Williams, C, Ruparelia, AA, Maisonobe, T, Peduto, AJ, Reddel, SW, Lek, M, Tukainen, T, Cummings, BB, Joshi, H, Nectoux, J, Brammah, S, Deleuze, J-F, Ing, VO, Ramm, G, Ardicli, D, Nowak, KJ, Talim, B, Topaloglu, H, Laing, NG, North, KN, MacArthur, DG, Friant, S, Clarke, NF, Bryson-Richardson, RJ, Bonnemann, CG, Laporte, J & Cooper, ST 2016, 'Variants in the oxidoreductase PYROXD1 cause early-onset myopathy with internalized nuclei and myofibrillar disorganization', American Journal of Human Genetics, pp. 1086-1105. https://doi.org/10.1016/j.ajhg.2016.09.005

Variants in the oxidoreductase PYROXD1 cause early-onset myopathy with internalized nuclei and myofibrillar disorganization. / O'Grady, Gina L; Best, Heather A; Sztal, Tamar E; Schartner, Vanessa; Sanjuan-Vazquez, Myriam; Donkervoort, Sandra; Neto, Osorio Abath; Sutton, Roger Bryan; Ilkovski, Biljana; Romero, Norma Beatriz; Stojkovic, Tanya; Dastgir, Jahannaz; Waddell, Leigh B; Boland, Anne; Hu, Ying; Williams, Caitlin; Ruparelia, Avnika A; Maisonobe, Thierry; Peduto, Anthony J; Reddel, Stephen W; Lek, Monkol; Tukainen, Taru; Cummings, Beryl B; Joshi, Himanshu; Nectoux, Juliette; Brammah, Susan; Deleuze, Jean-Francois; Ing, Viola Oorschot; Ramm, Georg; Ardicli, Didem; Nowak, Kristen J; Talim, Beril; Topaloglu, Haluk; Laing, Nigel G; North, Kathryn N; MacArthur, Daniel G; Friant, Sylvie; Clarke, Nigel F; Bryson-Richardson, Robert J; Bonnemann, Carsten G; Laporte, Jocelyn; Cooper, Sandra T.

In: American Journal of Human Genetics, 03.11.2016, p. 1086-1105.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Variants in the oxidoreductase PYROXD1 cause early-onset myopathy with internalized nuclei and myofibrillar disorganization

AU - O'Grady, Gina L

AU - Best, Heather A

AU - Sztal, Tamar E

AU - Schartner, Vanessa

AU - Sanjuan-Vazquez, Myriam

AU - Donkervoort, Sandra

AU - Neto, Osorio Abath

AU - Sutton, Roger Bryan

AU - Ilkovski, Biljana

AU - Romero, Norma Beatriz

AU - Stojkovic, Tanya

AU - Dastgir, Jahannaz

AU - Waddell, Leigh B

AU - Boland, Anne

AU - Hu, Ying

AU - Williams, Caitlin

AU - Ruparelia, Avnika A

AU - Maisonobe, Thierry

AU - Peduto, Anthony J

AU - Reddel, Stephen W

AU - Lek, Monkol

AU - Tukainen, Taru

AU - Cummings, Beryl B

AU - Joshi, Himanshu

AU - Nectoux, Juliette

AU - Brammah, Susan

AU - Deleuze, Jean-Francois

AU - Ing, Viola Oorschot

AU - Ramm, Georg

AU - Ardicli, Didem

AU - Nowak, Kristen J

AU - Talim, Beril

AU - Topaloglu, Haluk

AU - Laing, Nigel G

AU - North, Kathryn N

AU - MacArthur, Daniel G

AU - Friant, Sylvie

AU - Clarke, Nigel F

AU - Bryson-Richardson, Robert J

AU - Bonnemann, Carsten G

AU - Laporte, Jocelyn

AU - Cooper, Sandra T

PY - 2016/11/3

Y1 - 2016/11/3

N2 - 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.

AB - 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.

U2 - 10.1016/j.ajhg.2016.09.005

DO - 10.1016/j.ajhg.2016.09.005

M3 - Article

SP - 1086

EP - 1105

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

ER -