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Am J Hum Genet. 2017 Nov 2;101(5):856-865. doi: 10.1016/j.ajhg.2017.09.020.

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

Author information

1
Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada.
2
Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, and Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
3
Faculty of Medicine and Health University of Leeds, Leeds LS2 9JT, UK.
4
Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA.
5
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
6
Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Rush University, Chicago, IL 60612, USA.
7
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
8
Department of Radiology, Bradford Royal Infirmary, Duckworth Lane, Bradford BD9 6RJ, UK.
9
Comprehensive Epilepsy Program, Jane and John Justin Neuroscience Center, Cook Children's Medical Center, Fort Worth, TX 76104, USA.
10
Sheffield Children's Hospital NHS Foundation Trust, Western Bank, Sheffield S10 2TH, UK.
11
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
12
Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland; Department of Child Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Hospital District of Helsinki and Uusimaa, 00029 Helsinki, Finland.
13
Department of Child Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Hospital District of Helsinki and Uusimaa, 00029 Helsinki, Finland.
14
Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland; Molecular and Clinical Sciences Research Institute, St. George's, University of London, Cranmer Terrace, London SW17 0RE, UK.
15
Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada; Department of Pediatrics, University of Montreal, Montreal, QC H3T 1J4, Canada. Electronic address: p.campeau@umontreal.ca.

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.

KEYWORDS:

GPAA1; GPI; alkaline phosphatase; epilepsy; glycosylphosphatidylinositol; osteopenia; seizures

PMID:
29100095
PMCID:
PMC5673666
DOI:
10.1016/j.ajhg.2017.09.020
[Indexed for MEDLINE]
Free PMC Article

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