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PIGG variant pathogenicity assessment reveals characteristic features within 19 families.
Tremblay-Laganière, Camille; Maroofian, Reza; Nguyen, Thi Tuyet Mai; Karimiani, Ehsan Ghayoor; Kirmani, Salman; Akbar, Fizza; Ibrahim, Shahnaz; Afroze, Bushra; Doosti, Mohammad; Ashrafzadeh, Farah; Babaei, Meisam; Efthymiou, Stephanie; Christoforou, Marilena; Sultan, Tipu; Ladda, Roger L; McLaughlin, Heather M; Truty, Rebecca; Mahida, Sonal; Cohen, Julie S; Baranano, Kristin; Ismail, Fatima Y; Patel, Millan S; Lehman, Anna; Edmondson, Andrew C; Nagy, Amanda; Walker, Melissa A; Mercimek-Andrews, Saadet; Maki, Yuta; Sachdev, Rani; Macintosh, Rebecca; Palmer, Elizabeth E; Mancini, Grazia M S; Barakat, Tahsin Stefan; Steinfeld, Robert; Rüsch, Christina T; Stettner, Georg M; Wagner, Matias; Wortmann, Saskia B; Kini, Usha; Brady, Angela F; Stals, Karen L; Ismayilova, Naila; Ellard, Sian; Bernardo, Danilo; Nugent, Kimberly; McLean, Scott D; Antonarakis, Stylianos E; Houlden, Henry; Kinoshita, Taroh; Campeau, Philippe M.
Afiliação
  • Tremblay-Laganière C; Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and University of Montreal, Montreal, QC, Canada.
  • Maroofian R; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
  • Nguyen TTM; Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and University of Montreal, Montreal, QC, Canada.
  • Karimiani EG; Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's Hospital, University of London, London, UK.
  • Kirmani S; Next Generation Genetic Polyclinic, Mashhad, Iran.
  • Akbar F; Department of Pediatrics & Child Health, Aga Khan University, Karachi, Pakistan.
  • Ibrahim S; Department of Pediatrics & Child Health, Aga Khan University, Karachi, Pakistan.
  • Afroze B; Department of Pediatrics & Child Health, Aga Khan University, Karachi, Pakistan.
  • Doosti M; Department of Pediatrics & Child Health, Aga Khan University, Karachi, Pakistan.
  • Ashrafzadeh F; Next Generation Genetic Polyclinic, Mashhad, Iran.
  • Babaei M; Department of Pediatric Neurology, Mashhad University of Medical Sciences, Mashhad, Iran.
  • Efthymiou S; Department of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd, Iran.
  • Christoforou M; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
  • Sultan T; Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
  • Ladda RL; Department of Pediatric Neurology, Institute of Child Health, The Children's Hospital Lahore, Lahore, Pakistan.
  • McLaughlin HM; Department of Pediatrics, Milton S Hershey Medical Centre, Hershey, PA, USA.
  • Truty R; Invitae Corporation, San Francisco, CA, USA.
  • Mahida S; Invitae Corporation, San Francisco, CA, USA.
  • Cohen JS; Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
  • Baranano K; Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
  • Ismail FY; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Patel MS; Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
  • Lehman A; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Edmondson AC; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Nagy A; Department of Pediatrics, United Arab Emirates University, Al Ain, UAE.
  • Walker MA; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
  • Mercimek-Andrews S; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
  • Maki Y; Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • Sachdev R; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
  • Macintosh R; Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
  • Palmer EE; Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.
  • Mancini GMS; Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Stollery Children's Hospital, Alberta Health Services, Edmonton, AB, Canada.
  • Barakat TS; Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan.
  • Steinfeld R; Project Research Center for Fundamental Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan.
  • Rüsch CT; Sydney Children's Hospital, Centre for Clinical Genetics, Sydney Children's Hospital, High St, Randwick, UK.
  • Stettner GM; School of Women's and Children's Health, University of New South Wales, High St, Randwick, UK.
  • Wagner M; Sydney Children's Hospital, Centre for Clinical Genetics, Sydney Children's Hospital, High St, Randwick, UK.
  • Wortmann SB; Sydney Children's Hospital, Centre for Clinical Genetics, Sydney Children's Hospital, High St, Randwick, UK.
  • Kini U; School of Women's and Children's Health, University of New South Wales, High St, Randwick, UK.
  • Brady AF; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands, CA, Rotterdam, The Netherlands.
  • Stals KL; Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands, CA, Rotterdam, The Netherlands.
  • Ismayilova N; Department of Pediatric Neurology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
  • Ellard S; Department of Pediatric Neurology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
  • Bernardo D; Department of Pediatric Neurology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
  • Nugent K; Institute of Human Genetics, School of Medicine, Technical University Munich, Munich, Germany.
  • McLean SD; Institute for Neurogenomics Helmholtz Zentrum München, Neuherberg, Germany.
  • Antonarakis SE; University Children's Hospital, Paracelsus Medical School, Salzburg, Austria.
  • Houlden H; Amalias Children's Hospital, RadboudUMC, Nijmegen, the Netherlands.
  • Kinoshita T; Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford, UK.
  • Campeau PM; North West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Harrow, UK.
Genet Med ; 23(10): 1873-1881, 2021 10.
Article em En | MEDLINE | ID: mdl-34113002
ABSTRACT

PURPOSE:

Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized.

METHODS:

We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system.

RESULTS:

Phenotypic analysis of reported individuals reveals shared PIGG deficiency-associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder.

CONCLUSION:

This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosfotransferases (Aceptor do Grupo Álcool) / Transtorno do Espectro Autista / Deficiência Intelectual Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Fosfotransferases (Aceptor do Grupo Álcool) / Transtorno do Espectro Autista / Deficiência Intelectual Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article