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

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

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

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

Authors

Thi Tuyet Mai Nguyen¹, Yoshiko Murakami², Eamonn Sheridan³, Sophie Ehresmann¹, Justine Rousseau¹, Anik St-Denis¹, Guoliang Chai⁴, Norbert F Ajeawung¹, Laura Fairbrother⁵, Tyler Reimschisel⁵, Alexandra Bateman⁵, Elizabeth Berry-Kravis⁶, Fan Xia⁷, Jessica Tardif¹, David A Parry³, Clare V Logan³, Christine Diggle³, Christopher P Bennett³, Louise Hattingh⁸, Jill A Rosenfeld⁷, Michael Scott Perry⁹, Michael J Parker¹⁰, Françoise Le Deist¹, Maha S Zaki¹¹, Erika Ignatius¹², Pirjo Isohanni¹², Tuula Lönnqvist¹³, Christopher J Carroll¹⁴, Colin A Johnson³, Joseph G Gleeson⁴, Taroh Kinoshita², Philippe M Campeau¹⁵

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: 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.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.

MeSH terms

Acyltransferases / genetics*
Adolescent
Adult
Alleles
Atrophy / genetics*
Bone Diseases, Metabolic / genetics*
Cerebellum / pathology
Child
Child, Preschool
Developmental Disabilities / genetics*
Epilepsy / genetics*
Exome / genetics
Female
Fibroblasts / pathology
Glycosylphosphatidylinositols / genetics
Humans
Male
Membrane Glycoproteins / genetics*
Muscle Hypotonia / genetics
Mutation / genetics*
Pedigree
RNA, Messenger / genetics
Seizures / genetics

Substances

GPAA1 protein, human
Glycosylphosphatidylinositols
Membrane Glycoproteins
RNA, Messenger
Acyltransferases
COOH-terminal signal transamidase

Abstract

MeSH terms

Substances

Grants and funding