2. Academic Validation
  3. 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

  • Am J Hum Genet. 2017 Nov 2;101(5):856-865. doi: 10.1016/j.ajhg.2017.09.020.
Thi Tuyet Mai Nguyen 1,  Yoshiko Murakami 2,  Eamonn Sheridan 3,  Sophie Ehresmann 1,  Justine Rousseau 1,  Anik St-Denis 1,  Guoliang Chai 4,  Norbert F Ajeawung 1,  Laura Fairbrother 5,  Tyler Reimschisel 5,  Alexandra Bateman 5,  Elizabeth Berry-Kravis 6,  Fan Xia 7,  Jessica Tardif 1,  David A Parry 3,  Clare V Logan 3,  Christine Diggle 3,  Christopher P Bennett 3,  Louise Hattingh 8,  Jill A Rosenfeld 7,  Michael Scott Perry 9,  Michael J Parker 10,  Françoise Le Deist 1,  Maha S Zaki 11,  Erika Ignatius 12,  Pirjo Isohanni 12,  Tuula Lönnqvist 13,  Christopher J Carroll 14,  Colin A Johnson 3,  Joseph G Gleeson 4,  Taroh Kinoshita 2,  Philippe M Campeau 15
Affiliations

Affiliations

  • 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: [email protected].
PMID: 29100095 DOI: 10.1016/j.ajhg.2017.09.020
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.

Keywords

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

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