%0 Journal Article
%T Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia
%A Alexandra Bateman
%A Anik St-Denis
%A Christine Diggle
%A Christopher J. Carroll
%A Christopher P. Bennett
%A Clare V. Logan
%A Colin A. Johnson
%A David A. Parry
%A Eamonn Sheridan
%A Elizabeth Berry-Kravis
%A Erika Ignatius
%A Fan Xia
%A Fran£¿oise Le Deist
%A Guoliang Chai
%A Jessica Tardif
%A Jill A. Rosenfeld
%A Joseph G. Gleeson
%A Justine Rousseau
%A Laura Fairbrother
%A Louise Hattingh
%A Maha S. Zaki
%A Michael J. Parker
%A Michael Scott Perry
%A Norbert F. Ajeawung
%A Pirjo Isohanni
%A Sophie Ehresmann
%A Taroh Kinoshita
%A Thi Tuyet Mai Nguyen
%A Tuula L£¿nnqvist
%A Tyler Reimschisel
%A Yoshiko Murakami
%J Archive of "American Journal of Human Genetics".
%D 2017
%R 10.1016/j.ajhg.2017.09.020
%X 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
%K GPAA1
%K glycosylphosphatidylinositol
%K osteopenia
%K epilepsy
%K seizures GPAA1
%K glycosylphosphatidylinositol
%K GPI
%K alkaline phosphatase
%K osteopenia
%K epilepsy
%K seizures
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673666/