Title |
Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia
|
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Published in |
American Journal of Human Genetics, November 2017
|
DOI | 10.1016/j.ajhg.2017.09.020 |
Pubmed ID | |
Authors |
Thi Tuyet Mai Nguyen, Yoshiko Murakami, Eamonn Sheridan, Sophie Ehresmann, Justine Rousseau, Anik St-Denis, Guoliang Chai, Norbert F. Ajeawung, Laura Fairbrother, Tyler Reimschisel, Alexandra Bateman, Elizabeth Berry-Kravis, Fan Xia, Jessica Tardif, David A. Parry, Clare V. Logan, Christine Diggle, Christopher P. Bennett, Louise Hattingh, Jill A. Rosenfeld, Michael Scott Perry, Michael J. Parker, Françoise Le Deist, Maha S. Zaki, Erika Ignatius, Pirjo Isohanni, Tuula Lönnqvist, Christopher J. Carroll, Colin A. Johnson, Joseph G. Gleeson, Taroh Kinoshita, Philippe M. Campeau |
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. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United Kingdom | 3 | 21% |
United States | 2 | 14% |
Italy | 1 | 7% |
Finland | 1 | 7% |
Unknown | 7 | 50% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 7 | 50% |
Scientists | 5 | 36% |
Practitioners (doctors, other healthcare professionals) | 1 | 7% |
Science communicators (journalists, bloggers, editors) | 1 | 7% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 62 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 12 | 19% |
Student > Ph. D. Student | 8 | 13% |
Student > Master | 7 | 11% |
Student > Doctoral Student | 5 | 8% |
Student > Bachelor | 5 | 8% |
Other | 11 | 18% |
Unknown | 14 | 23% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 17 | 27% |
Medicine and Dentistry | 9 | 15% |
Neuroscience | 9 | 15% |
Agricultural and Biological Sciences | 5 | 8% |
Psychology | 2 | 3% |
Other | 5 | 8% |
Unknown | 15 | 24% |