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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; Murakami, Yoshiko; Sheridan, Eamonn; Ehresmann, Sophie; Rousseau, Justine; St-Denis, Anik; Chai, Guoliang; Ajeawung, Norbert F; Fairbrother, Laura; Reimschisel, Tyler; Bateman, Alexandra; Berry-Kravis, Elizabeth; Xia, Fan; Tardif, Jessica; Parry, David A; Logan, Clare V; Diggle, Christine; Bennett, Christopher P; Hattingh, Louise; Rosenfeld, Jill A; Perry, Michael Scott; Parker, Michael J; Le Deist, Françoise; Zaki, Maha S; Ignatius, Erika; Isohanni, Pirjo; Lönnqvist, Tuula; Carroll, Christopher J; Johnson, Colin A; Gleeson, Joseph G; Kinoshita, Taroh; Campeau, Philippe M.
Afiliación
  • Nguyen TTM; Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada.
  • Murakami Y; Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, and Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
  • Sheridan E; Faculty of Medicine and Health University of Leeds, Leeds LS2 9JT, UK.
  • Ehresmann S; Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada.
  • Rousseau J; Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada.
  • St-Denis A; Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada.
  • Chai G; Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA.
  • Ajeawung NF; Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada.
  • Fairbrother L; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Reimschisel T; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Bateman A; Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • Berry-Kravis E; Departments of Pediatrics, Neurological Sciences, and Biochemistry, Rush University Medical Center, Rush University, Chicago, IL 60612, USA.
  • Xia F; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Tardif J; Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada.
  • Parry DA; Faculty of Medicine and Health University of Leeds, Leeds LS2 9JT, UK.
  • Logan CV; Faculty of Medicine and Health University of Leeds, Leeds LS2 9JT, UK.
  • Diggle C; Faculty of Medicine and Health University of Leeds, Leeds LS2 9JT, UK.
  • Bennett CP; Faculty of Medicine and Health University of Leeds, Leeds LS2 9JT, UK.
  • Hattingh L; Department of Radiology, Bradford Royal Infirmary, Duckworth Lane, Bradford BD9 6RJ, UK.
  • Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • Perry MS; Comprehensive Epilepsy Program, Jane and John Justin Neuroscience Center, Cook Children's Medical Center, Fort Worth, TX 76104, USA.
  • Parker MJ; Sheffield Children's Hospital NHS Foundation Trust, Western Bank, Sheffield S10 2TH, UK.
  • Le Deist F; Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada.
  • Zaki MS; Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
  • Ignatius E; 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.
  • Isohanni P; 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.
  • Lönnqvist T; Department of Child Neurology, Children's Hospital, University of Helsinki and Helsinki University Hospital, Hospital District of Helsinki and Uusimaa, 00029 Helsinki, Finland.
  • Carroll CJ; 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.
  • Johnson CA; Faculty of Medicine and Health University of Leeds, Leeds LS2 9JT, UK.
  • Gleeson JG; Howard Hughes Medical Institute, Rady Children's Institute for Genomic Medicine, Department of Neuroscience, University of California, San Diego, San Diego, CA 92093, USA.
  • Kinoshita T; Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, and Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
  • Campeau PM; 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.
Am J Hum Genet ; 101(5): 856-865, 2017 Nov 02.
Article en En | MEDLINE | ID: mdl-29100095
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Atrofia / Enfermedades Óseas Metabólicas / Aciltransferasas / Glicoproteínas de Membrana / Discapacidades del Desarrollo / Epilepsia / Mutación Tipo de estudio: Prognostic_studies Límite: Adolescent / Adult / Child / Child, preschool / Female / Humans / Male Idioma: En Revista: Am J Hum Genet Año: 2017 Tipo del documento: Article País de afiliación: Canadá

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Atrofia / Enfermedades Óseas Metabólicas / Aciltransferasas / Glicoproteínas de Membrana / Discapacidades del Desarrollo / Epilepsia / Mutación Tipo de estudio: Prognostic_studies Límite: Adolescent / Adult / Child / Child, preschool / Female / Humans / Male Idioma: En Revista: Am J Hum Genet Año: 2017 Tipo del documento: Article País de afiliación: Canadá