Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia.

Abstract

Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs∗102] and c.920delG [p.Gly307Alafs∗11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.

• Authors: Thi Tuyet Mai Nguyen, Yoshiko Murakami, Eamonn Sheridan, Sophie Ehresmann, Justine Rousseau, Anik St-Denis, Guoliang Chai, Norbert F Ajeawung, Laura Fairbrother, Tyler Reimschisel, Alexandra Bateman, Elizabeth Berry-Kravis, Fan Xia, Jessica Tardif, David A Parry, Clare V Logan, Christine Diggle, Christopher P Bennett, Louise Hattingh, Jill A Rosenfeld, Michael Scott Perry, Michael J Parker, Françoise Le Deist, Maha S Zaki, Erika Ignatius, Pirjo Isohanni, Tuula Lönnqvist, Christopher J Carroll, Colin A Johnson, Joseph G Gleeson, Taroh Kinoshita, Philippe M Campeau
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 101 Issue 5 Pg. 856-865 (Nov 02 2017) ISSN: 1537-6605 [Electronic] United States
• PMID: 29100095 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Chemical References

• GPAA1 protein, human
• Glycosylphosphatidylinositols
• Membrane Glycoproteins
• RNA, Messenger
• Acyltransferases
• COOH-terminal signal transamidase

Topics

• Acyltransferases (genetics)
• Adolescent
• Adult
• Alleles
• Atrophy (genetics)
• Bone Diseases, Metabolic (genetics)
• Cerebellum (pathology)
• Child
• Child, Preschool
• Developmental Disabilities (genetics)
• Epilepsy (genetics)
• Exome (genetics)
• Female
• Fibroblasts (pathology)
• Glycosylphosphatidylinositols (genetics)
• Humans
• Male
• Membrane Glycoproteins (genetics)
• Muscle Hypotonia (genetics)
• Mutation (genetics)
• Pedigree
• RNA, Messenger (genetics)
• Seizures (genetics)