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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.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.

SUBMITTER: Nguyen TTM 

PROVIDER: S-EPMC5673666 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Nguyen Thi Tuyet Mai TTM   Murakami Yoshiko Y   Sheridan Eamonn E   Ehresmann Sophie S   Rousseau Justine J   St-Denis Anik A   Chai Guoliang G   Ajeawung Norbert F NF   Fairbrother Laura L   Reimschisel Tyler T   Bateman Alexandra A   Berry-Kravis Elizabeth E   Xia Fan F   Tardif Jessica J   Parry David A DA   Logan Clare V CV   Diggle Christine C   Bennett Christopher P CP   Hattingh Louise L   Rosenfeld Jill A JA   Perry Michael Scott MS   Parker Michael J MJ   Le Deist Françoise F   Zaki Maha S MS   Ignatius Erika E   Isohanni Pirjo P   Lönnqvist Tuula T   Carroll Christopher J CJ   Johnson Colin A CA   Gleeson Joseph G JG   Kinoshita Taroh T   Campeau Philippe M PM  

American journal of human genetics 20171101 5


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 biosynt  ...[more]

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