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.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.

Clinical variability in inherited glycosylphosphatidylinositol deficiency disorders

“…Most patients with GPAA1 mutations presented with early‐onset seizures, hypotonia and global developmental delay which overlapped with those identified in individuals with PIGT mutations. In addition, these patients also suffered from osteopenia and cerebellar atrophy …”

“…In addition, these patients also suffered from osteopenia and cerebellar atrophy. 37 3.16 | PGAP1 PGAP1 stands for "post-GPI attachment to proteins 1" and is located in the ER. After the GPI anchors have been successfully attached to the proteins by the GPI transamidase enzyme, their acyl chain is cleaved from the inositol ring.…”

Molecular analysis of glycosylphosphatidylinositol anchor deficient aerolysin resistant isolates in gulf war i veterans exposed to depleted uranium

“…Also, rare GPIa negative cells are found in the blood and bone marrow of healthy individuals (Nafa et al, 1998;Hu et al, 2005). Germinal mutations in all but seven of the 26 GPIa pathway genes have been demonstrated to be the cause a number of genetic diseases from severe forms with multiple malformations to milder forms with intellectual disability (Kim et al, 2000;Kranz et al, 2001;Schenk et al, 2001;Garcia-Silva et al, 2004;Almeida et al, 2006;Lefeber et al, 2009;Krawitz et al, 2010Krawitz et al, , 2012Maydan et al, 2011;Barone et al, 2012;Ng et al, 2012;Thompson et al, 2012;Kvarnung et al, 2013;Chiyonobu et al, 2014;Martin et al, 2014;Nakamura et al, 2014;Nakashima et al, 2014;Ohba et al, 2014;Fujiwara et al, 2015;Ilkovski et al, 2015;Lam et al, 2015;Fleming et al, 2016;Hogrebe et al, 2016;Khayat et al, 2016;Makrythanasis et al, 2016;Edvardson et al, 2017;Johnstone et al, 2017;Nguyen et al, 2017Nguyen et al, , 2018Pagnamenta et al, 2018).…”

Longitudinal study of t‐cell somatic mutations conferring glycosylphosphatidylinositol‐anchor deficiency in gulf war I veterans exposed to depleted uranium

“…In regards to the second argument for mutation in PIGA being the only event that can produce GPIa deficiency because it is the only locus where a null phenotype can be produced by a single hit that is only true for individuals who are homozygous wild type for all other genes in the GPIa pathway. However, in humans, genetic conditions are known which are the result of homozygous mutations in one of the GPIa pathway genes (PIGC, PIGG, PIGH, PIGL, PIGM, PIGN, PIGO, PIGP, PIGQ, PIGT, PIGV, PIGW, PIGY, GPAA1, DPM1, DPM2, DPM3, and MPDU1) (Kim et al, 2000;Kranz et al, 2001;Schenk et al, 2001;Garcia-Silva et al, 2004;Almeida et al, 2006;Lefeber et al, 2009;Krawitz et al, 2010;Maydan et al, 2011;Barone et al, 2012;Krawitz et al, 2012;Ng et al, 2012;Thompson et al, 2012;Kvarnung et al, 2013;Chiyonobu et al, 2014;Martin et al, 2014;Nakamura et al, 2014;Nakashima et al, 2014;Ohba et al, 2014;Fujiwara et al, 2015;Ilkovski et al, 2015;Lam et al, 2015;Fleming et al, 2016;Hogrebe et al, 2016;Khayat et al, 2016;Makrythanasis et al, 2016;Edvardson et al, 2017;Johnstone et al, 2017;Nguyen et al, 2017;Nguyen et al, 2018;Pagnamenta et al, 2018). Clearly, heterozygosity for mutations will be present in the general population for each of these genes.…”