PIGG variant pathogenicity assessment reveals characteristic features within 19 families

Camille Tremblay-Laganière; Reza Maroofian; Thi Tuyet Mai Nguyen; Ehsan Ghayoor Karimiani; Salman Kirmani; Fizza Akbar; Shahnaz Ibrahim; Bushra Afroze; Mohammad Doosti; Farah Ashrafzadeh; Meisam Babaei; Stephanie Efthymiou; Marilena Christoforou; Tipu Sultan; Roger L Ladda; Heather M McLaughlin; Rebecca Truty; Sonal Mahida; Julie S Cohen; Kristin Baranano; Fatima Y Ismail; Millan S Patel; Anna Lehman; Andrew C Edmondson; Amanda Nagy; Melissa A Walker; Saadet Mercimek-Andrews; Yuta Maki; Rani Sachdev; Rebecca Macintosh; Elizabeth E Palmer; Grazia M S Mancini; Tahsin Stefan Barakat; Robert Steinfeld; Christina T Rüsch; Georg M Stettner; Matias Wagner; Saskia B Wortmann; Usha Kini; Angela F Brady; Karen L Stals; Naila Ismayilova; Sian Ellard; Danilo Bernardo; Kimberly Nugent; Scott D McLean; Stylianos E Antonarakis; Henry Houlden; Taroh Kinoshita; Philippe M Campeau; Yoshiko Murakami

doi:10.1038/s41436-021-01215-9

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. Epub 2021 Jun 10.

Authors

Camille Tremblay-Laganière¹, Reza Maroofian², Thi Tuyet Mai Nguyen¹, Ehsan Ghayoor Karimiani^{3

4}, Salman Kirmani⁵, Fizza Akbar⁵, Shahnaz Ibrahim⁵, Bushra Afroze⁵, Mohammad Doosti⁴, Farah Ashrafzadeh⁶, Meisam Babaei⁷, Stephanie Efthymiou², Marilena Christoforou², Tipu Sultan⁸, Roger L Ladda⁹, Heather M McLaughlin¹⁰, Rebecca Truty¹⁰, Sonal Mahida¹¹, Julie S Cohen^{11

12}, Kristin Baranano^{11

12}, Fatima Y Ismail^{12

13}, Millan S Patel¹⁴, Anna Lehman¹⁴, Andrew C Edmondson¹⁵, Amanda Nagy¹⁶, Melissa A Walker¹⁶, Saadet Mercimek-Andrews^{17

18}, Yuta Maki^{19

20}, Rani Sachdev^{21

22}, Rebecca Macintosh²¹, Elizabeth E Palmer^{21

22}, Grazia M S Mancini²³, Tahsin Stefan Barakat²³, Robert Steinfeld²⁴, Christina T Rüsch²⁴, Georg M Stettner²⁴, Matias Wagner^{25

26}, Saskia B Wortmann^{27

28}, Usha Kini²⁹, Angela F Brady³⁰, Karen L Stals³¹, Naila Ismayilova³², Sian Ellard^{31

33}, Danilo Bernardo³⁴, Kimberly Nugent³⁵, Scott D McLean³⁵, Stylianos E Antonarakis³⁶, Henry Houlden², Taroh Kinoshita^{37

38}, Philippe M Campeau³⁹, Yoshiko Murakami^{40

41}

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].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Autism Spectrum Disorder*
Humans
Intellectual Disability*
Membrane Proteins
Pedigree
Phosphotransferases (Alcohol Group Acceptor) / genetics*
Seizures
Virulence

Substances

Membrane Proteins
PIGO protein, human
PIGG protein, human
Phosphotransferases (Alcohol Group Acceptor)

Abstract

Publication types

MeSH terms

Substances

Grants and funding