TY - JOUR
T1 - PIGG variant pathogenicity assessment reveals characteristic features within 19 families
AU - Tremblay-Laganière, Camille
AU - Maroofian, Reza
AU - Nguyen, Thi Tuyet Mai
AU - Karimiani, Ehsan Ghayoor
AU - Kirmani, Salman
AU - Akbar, Fizza
AU - Ibrahim, Shahnaz
AU - Afroze, Bushra
AU - Doosti, Mohammad
AU - Ashrafzadeh, Farah
AU - Babaei, Meisam
AU - Efthymiou, Stephanie
AU - Christoforou, Marilena
AU - Sultan, Tipu
AU - Ladda, Roger L.
AU - McLaughlin, Heather M.
AU - Truty, Rebecca
AU - Mahida, Sonal
AU - Cohen, Julie S.
AU - Baranano, Kristin
AU - Ismail, Fatima Y.
AU - Patel, Millan S.
AU - Lehman, Anna
AU - Edmondson, Andrew C.
AU - Nagy, Amanda
AU - Walker, Melissa A.
AU - Mercimek-Andrews, Saadet
AU - Maki, Yuta
AU - Sachdev, Rani
AU - Macintosh, Rebecca
AU - Palmer, Elizabeth E.
AU - Mancini, Grazia M.S.
AU - Barakat, Tahsin Stefan
AU - Steinfeld, Robert
AU - Rüsch, Christina T.
AU - Stettner, Georg M.
AU - Wagner, Matias
AU - Wortmann, Saskia B.
AU - Kini, Usha
AU - Brady, Angela F.
AU - Stals, Karen L.
AU - Ismayilova, Naila
AU - Ellard, Sian
AU - Bernardo, Danilo
AU - Nugent, Kimberly
AU - McLean, Scott D.
AU - Antonarakis, Stylianos E.
AU - Houlden, Henry
AU - Kinoshita, Taroh
AU - Campeau, Philippe M.
AU - Murakami, Yoshiko
N1 - Funding Information:
This work is supported by Canadian Institutes of Health Research (CIHR) and Fonds de Recherche du Québec–Santé (FRQS) awards to P.M.C. We thank Keiko Kinoshita, Saori Umeshita, Kae Imanishi (Osaka University) for technical help. T.S.B. is supported by the Netherlands Organisation for Scientific Research (ZonMW Veni, grant 91617021), a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation, an Erasmus MC Fellowship 2017, and Erasmus MC Human Disease Model Award 2018. This work was supported by JSPS and MEXT KAKENHI grants (JP16H04753 and JP17H06422), and grants from AMED (20ek0109418h0002) and MHLW of Japan. Some families were collected as part of the SYNaPS Study Group collaboration funded by the Welcome Trust and strategic award (Synaptopathies) funding (WT093205 MA and WT104033AIA). This research was conducted as part of the Queen Square Genomics group at University College London, supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. Family 13 was identified in the CAUSES Study, funded by British Columbia Children’s Hospital Foundation and Genome BC.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85107468505&partnerID=8YFLogxK
U2 - 10.1038/s41436-021-01215-9
DO - 10.1038/s41436-021-01215-9
M3 - Article
C2 - 34113002
AN - SCOPUS:85107468505
SN - 1098-3600
VL - 23
SP - 1873
EP - 1881
JO - Genetics in Medicine
JF - Genetics in Medicine
IS - 10
ER -