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

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.