PIGG variant pathogenicity assessment reveals characteristic features within 19 families.

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.

• Authors: 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
• Journal: Genetics in medicine : official journal of the American College of Medical Genetics (Genet Med) Vol. 23 Issue 10 Pg. 1873-1881 (10 2021) ISSN: 1530-0366 [Electronic] United States
• PMID: 34113002 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.

Chemical References

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

Topics

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