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Impact of PYROXD1 deficiency on cellular respiration and correlations with genetic analyses of limb-girdle muscular dystrophy in Saudi Arabia and Sudan.
Saha, Madhurima; Reddy, Hemakumar M; Salih, Mustafa A; Estrella, Elicia; Jones, Michael D; Mitsuhashi, Satomi; Cho, Kyung-Ah; Suzuki-Hatano, Silveli; Rizzo, Skylar A; Hamad, Muddathir H; Mukhtar, Maowia M; Hamed, Ahlam A; Elseed, Maha A; Lek, Monkol; Valkanas, Elise; MacArthur, Daniel G; Kunkel, Louis M; Pacak, Christina A; Draper, Isabelle; Kang, Peter B.
Afiliação
  • Saha M; Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine , Gainesville, Florida.
  • Reddy HM; Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine , Gainesville, Florida.
  • Salih MA; Division of Neurology, Department of Pediatrics, King Saud University , Riyadh , Saudi Arabia.
  • Estrella E; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School , Boston, Massachusetts.
  • Jones MD; Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine , Gainesville, Florida.
  • Mitsuhashi S; Department of Neurology, Boston Children's Hospital and Harvard Medical School , Boston, Massachusetts.
  • Cho KA; Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine , Gainesville, Florida.
  • Suzuki-Hatano S; Department of Pediatrics, University of Florida College of Medicine , Gainesville, Florida.
  • Rizzo SA; Division of Pediatric Neurology, Department of Pediatrics, University of Florida College of Medicine , Gainesville, Florida.
  • Hamad MH; Division of Neurology, Department of Pediatrics, King Saud University , Riyadh , Saudi Arabia.
  • Mukhtar MM; The Institute of Endemic Diseases, University of Khartoum , Khartoum , Sudan.
  • Hamed AA; Department of Paediatrics and Child Health, Faculty of Medicine, University of Khartoum , Khartoum , Sudan.
  • Elseed MA; Department of Paediatrics and Child Health, Faculty of Medicine, University of Khartoum , Khartoum , Sudan.
  • Lek M; Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School , Boston, Massachusetts.
  • Valkanas E; Broad Institute of the Massachusetts Institute of Technology and Harvard University , Cambridge, Massachusetts.
  • MacArthur DG; Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School , Boston, Massachusetts.
  • Kunkel LM; Broad Institute of the Massachusetts Institute of Technology and Harvard University , Cambridge, Massachusetts.
  • Pacak CA; Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School , Boston, Massachusetts.
  • Draper I; Broad Institute of the Massachusetts Institute of Technology and Harvard University , Cambridge, Massachusetts.
  • Kang PB; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School , Boston, Massachusetts.
Physiol Genomics ; 50(11): 929-939, 2018 11 01.
Article em En | MEDLINE | ID: mdl-30345904
ABSTRACT
Next-generation sequencing is commonly used to screen for pathogenic mutations in families with Mendelian disorders, but due to the pace of discoveries, gaps have widened for some diseases between genetic and pathophysiological knowledge. We recruited and analyzed 16 families with limb-girdle muscular dystrophy (LGMD) of Arab descent from Saudi Arabia and Sudan who did not have confirmed genetic diagnoses. The analysis included both traditional and next-generation sequencing approaches. Cellular and metabolic studies were performed on Pyroxd1 siRNA C2C12 myoblasts and controls. Pathogenic mutations were identified in eight of the 16 families. One Sudanese family of Arab descent residing in Saudi Arabia harbored a homozygous c.464A>G, p.Asn155Ser mutation in PYROXD1, a gene recently reported in association with myofibrillar myopathy and whose protein product reduces thiol residues. Pyroxd1 deficiency in murine C2C12 myoblasts yielded evidence for impairments of cellular proliferation, migration, and differentiation, while CG10721 (Pyroxd1 fly homolog) knockdown in Drosophila yielded a lethal phenotype. Further investigations indicated that Pyroxd1 does not localize to mitochondria, yet Pyroxd1 deficiency is associated with decreased cellular respiration. This study identified pathogenic mutations in half of the LGMD families from the cohort, including one in PYROXD1. Developmental impairments were demonstrated in vitro for Pyroxd1 deficiency and in vivo for CG10721 deficiency, with reduced metabolic activity in vitro for Pyroxd1 deficiency.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Distrofia Muscular do Cíngulo dos Membros / Oxirredutases atuantes sobre Doadores de Grupo Enxofre / Mutação Tipo de estudo: Prognostic_studies Limite: Adult / Animals / Female / Humans / Male País/Região como assunto: Africa / Asia Idioma: En Revista: Physiol Genomics Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Distrofia Muscular do Cíngulo dos Membros / Oxirredutases atuantes sobre Doadores de Grupo Enxofre / Mutação Tipo de estudo: Prognostic_studies Limite: Adult / Animals / Female / Humans / Male País/Região como assunto: Africa / Asia Idioma: En Revista: Physiol Genomics Assunto da revista: BIOLOGIA MOLECULAR Ano de publicação: 2018 Tipo de documento: Article