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Tremblay-Laganière, C.* ; Maroofian, R.* ; Nguyen, T.T.M.* ; Karimiani, E.G.* ; Kirmani, S.* ; Akbar, F.* ; Ibrahim, S.* ; Afroze, B.* ; Doosti, M.* ; Ashrafzadeh, F.* ; Babaei, M.* ; Efthymiou, S.* ; Christoforou, M.* ; Sultan, T.* ; Ladda, R.L.* ; McLaughlin, H.M.* ; Truty, R.* ; Mahida, S.* ; Cohen, J.S.* ; Baranano, K.* ; Ismail, F.Y.* ; Patel, M.S.* ; Lehman, A.* ; Edmondson, A.C.* ; Nagy, A.* ; Walker, M.A.* ; Mercimek-Andrews, S.* ; Maki, Y.* ; Sachdev, R.* ; Macintosh, R.* ; Palmer, E.E.* ; Mancini, G.M.S.* ; Barakat, T.S.* ; Steinfeld, R.* ; Rüsch, C.T.* ; Stettner, G.M.* ; Wagner, M. ; Wortmann, S.B.* ; Kini, U.* ; Brady, A.F.* ; Stals, K.L.* ; Ismayilova, N.* ; Ellard, S.* ; Bernardo, D.* ; Nugent, K.* ; McLean, S.D.* ; Antonarakis, S.E.* ; Houlden, H.* ; Kinoshita, T.* ; Campeau, P.M.* ; Murakami, Y.*

PIGG variant pathogenicity assessment reveals characteristic features within 19 families.

Genet. Med. 23, 1873-1881 (2021)
Postprint Forschungsdaten DOI PMC
Open Access Green
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Gpi; Hyperphosphatasia; Diagnosis
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Zeitschrift Genetics in Medicine
Quellenangaben Band: 23, Heft: 10, Seiten: 1873-1881 Artikelnummer: , Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Baltimore, Md.
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
Förderungen Genome BC
Erasmus MC Human Disease Model Award 2018
Erasmus MC Fellowship 2017
NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation
Netherlands Organisation for Scientific Research (ZonMW Veni)
Fonds de recherche du Quebec-Sante (FRQS)
Canadian Institutes of Health Research (CIHR)
Ministry of Education, Culture, Sports, Science and Technology
Japan Society for the Promotion of Science
JSPS
British Columbia Children's Hospital Foundation
National Institute for Health Research University College London Hospitals Biomedical Research Centre
strategic award (Synaptopathies) funding
Welcome Trust
MHLW of Japan
AMED
MEXT KAKENHI