Nguyen, TTM, Murakami, Y, Sheridan, E orcid.org/0000-0002-7237-6280 et al. (29 more authors) (2017) Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia. American Journal of Human Genetics, 101 (5). pp. 856-865. ISSN 0002-9297
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 protein) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT and PIGU (Phosphatidylinositol-glycan biosynthesis class K, S, T and U proteins). This complex orchestrates the attachment of the GPI anchor to the carboxyl 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 on five available individual samples showed that several GPI-anchored proteins had decreased cell surface abundance in leukocytes (FLAER, CD16, CD59) or fibroblasts (CD73, CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the GPI-anchored protein deficiency. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2017 American Society of Human Genetics. This is an author produced version of a paper published in American Journal of Human Genetics. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | GPAA1; glycosylphosphatidylinositol; GPI; alkaline phosphatase; osteopenia; epilepsy; seizures |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Inst of Biomed & Clin Sciences (LIBACS) (Leeds) > Genetics (LIBACS) (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 24 Oct 2017 15:29 |
Last Modified: | 02 May 2018 00:39 |
Status: | Published |
Publisher: | Elsevier (Cell Press) |
Identification Number: | 10.1016/j.ajhg.2017.09.020 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:122979 |