3 years ago

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

Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia
Fan Xia, Clare V. Logan, Philippe M. Campeau, Eamonn Sheridan, Colin A. Johnson, Jill A. Rosenfeld, Elizabeth Berry-Kravis, David A. Parry, Joseph G. Gleeson, Justine Rousseau, Tuula Lönnqvist, Françoise Le Deist, Erika Ignatius, Christopher P. Bennett, Christine Diggle, Sophie Ehresmann, Pirjo Isohanni, Yoshiko Murakami, Michael J. Parker, Anik St-Denis, Michael Scott Perry, Norbert F. Ajeawung, Laura Fairbrother, Taroh Kinoshita, Alexandra Bateman, Tyler Reimschisel, Jessica Tardif, Thi Tuyet Mai Nguyen, Christopher J. Carroll, Maha S. Zaki, Louise Hattingh, Guoliang Chai

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.Gln327Hisfs102] and c.920delG [p.Gly307Alafs11]), 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.

Publisher URL: http://www.cell.com/ajhg/fulltext/S0002-9297(17)30389-0

DOI: 10.1016/j.ajhg.2017.09.020

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