2. Academic Validation
  3. PIGG variant pathogenicity assessment reveals characteristic features within 19 families

PIGG variant pathogenicity assessment reveals characteristic features within 19 families

  • Genet Med. 2021 Oct;23(10):1873-1881. doi: 10.1038/s41436-021-01215-9.
Camille Tremblay-Laganière 1,  Reza Maroofian 2,  Thi Tuyet Mai Nguyen 1,  Ehsan Ghayoor Karimiani 3 4,  Salman Kirmani 5,  Fizza Akbar 5,  Shahnaz Ibrahim 5,  Bushra Afroze 5,  Mohammad Doosti 4,  Farah Ashrafzadeh 6,  Meisam Babaei 7,  Stephanie Efthymiou 2,  Marilena Christoforou 2,  Tipu Sultan 8,  Roger L Ladda 9,  Heather M McLaughlin 10,  Rebecca Truty 10,  Sonal Mahida 11,  Julie S Cohen 11 12,  Kristin Baranano 11 12,  Fatima Y Ismail 12 13,  Millan S Patel 14,  Anna Lehman 14,  Andrew C Edmondson 15,  Amanda Nagy 16,  Melissa A Walker 16,  Saadet Mercimek-Andrews 17 18,  Yuta Maki 19 20,  Rani Sachdev 21 22,  Rebecca Macintosh 21,  Elizabeth E Palmer 21 22,  Grazia M S Mancini 23,  Tahsin Stefan Barakat 23,  Robert Steinfeld 24,  Christina T Rüsch 24,  Georg M Stettner 24,  Matias Wagner 25 26,  Saskia B Wortmann 27 28,  Usha Kini 29,  Angela F Brady 30,  Karen L Stals 31,  Naila Ismayilova 32,  Sian Ellard 31 33,  Danilo Bernardo 34,  Kimberly Nugent 35,  Scott D McLean 35,  Stylianos E Antonarakis 36,  Henry Houlden 2,  Taroh Kinoshita 37 38,  Philippe M Campeau 39,  Yoshiko Murakami 40 41
Affiliations

Affiliations

  • 1 Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and University of Montreal, Montreal, QC, Canada.
  • 2 Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
  • 3 Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's Hospital, University of London, London, UK.
  • 4 Next Generation Genetic Polyclinic, Mashhad, Iran.
  • 5 Department of Pediatrics & Child Health, Aga Khan University, Karachi, Pakistan.
  • 6 Department of Pediatric Neurology, Mashhad University of Medical Sciences, Mashhad, Iran.
  • 7 Department of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd, Iran.
  • 8 Department of Pediatric Neurology, Institute of Child Health, The Children's Hospital Lahore, Lahore, Pakistan.
  • 9 Department of Pediatrics, Milton S Hershey Medical Centre, Hershey, PA, USA.
  • 10 Invitae Corporation, San Francisco, CA, USA.
  • 11 Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
  • 12 Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 13 Department of Pediatrics, United Arab Emirates University, Al Ain, UAE.
  • 14 Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
  • 15 Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 16 Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
  • 17 Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.
  • 18 Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Stollery Children's Hospital, Alberta Health Services, Edmonton, AB, Canada.
  • 19 Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan.
  • 20 Project Research Center for Fundamental Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan.
  • 21 Sydney Children's Hospital, Centre for Clinical Genetics, Sydney Children's Hospital, High St, Randwick, UK.
  • 22 School of Women's and Children's Health, University of New South Wales, High St, Randwick, UK.
  • 23 Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands, CA, Rotterdam, The Netherlands.
  • 24 Department of Pediatric Neurology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
  • 25 Institute of Human Genetics, School of Medicine, Technical University Munich, Munich, Germany.
  • 26 Institute for Neurogenomics Helmholtz Zentrum München, Neuherberg, Germany.
  • 27 University Children's Hospital, Paracelsus Medical School, Salzburg, Austria.
  • 28 Amalias Children's Hospital, RadboudUMC, Nijmegen, the Netherlands.
  • 29 Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford, UK.
  • 30 North West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Harrow, UK.
  • 31 Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
  • 32 Department of Paediatric Neurology, Chelsea and Westminster Hospital, London, UK.
  • 33 Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK.
  • 34 University of California San Francisco, Clinical Neurology, San Francisco, CA, UK.
  • 35 Department of Pediatrics, Baylor College of Medicine, The Children's Hospital of San Antonio, San Antonio, TX, USA.
  • 36 Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
  • 37 Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
  • 38 Department of Immunoglycobiology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
  • 39 Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and University of Montreal, Montreal, QC, Canada. [email protected].
  • 40 Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan. [email protected].
  • 41 Department of Immunoglycobiology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan. [email protected].
PMID: 34113002 DOI: 10.1038/s41436-021-01215-9
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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