title: Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies.
abstract: Glycosylphosphatidylinositol (GPI)-anchored proteins are ubiquitously expressed in the human body and are important for various functions at the cell surface. Mutations in many GPI biosynthesis genes have been described to date in patients with multi-system disease and together these constitute a subtype of congenital disorders of glycosylation. We used whole exome sequencing in two families to investigate the genetic basis of disease and used RNA and cellular studies to investigate the functional consequences of sequence variants in the PIGY gene. Two families with different phenotypes had homozygous recessive sequence variants in the GPI biosynthesis gene PIGY. Two sisters with c.137T>C (p.Leu46Pro) PIGY variants had multi-system disease including dysmorphism, seizures, severe developmental delay, cataracts and early death. There were significantly reduced levels of GPI-anchored proteins (CD55 and CD59) on the surface of patient-derived skin fibroblasts (∼20-50% compared with controls). In a second, consanguineous family, two siblings had moderate development delay and microcephaly. A homozygous PIGY promoter variant (c.-540G>A) was detected within a 7.7 Mb region of autozygosity. This variant was predicted to disrupt a SP1 consensus binding site and was shown to be associated with reduced gene expression. Mutations in PIGY can occur in coding and non-coding regions of the gene and cause variable phenotypes. This article contributes to understanding of the range of disease phenotypes and disease genes associated with deficiencies of the GPI-anchor biosynthesis pathway and also serves to highlight the potential importance of analysing variants detected in 5'-UTR regions despite their typically low coverage in exome data.
authors: Institute for Neuroscience and Muscle Research.
authors: Biljana
authors: B
authors: Ilkovski
authors: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford.
authors: Alistair T
authors: AT
authors: Pagnamenta
authors: Institute for Neuroscience and Muscle Research, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia.
authors: Gina L
authors: GL
authors: O'Grady
authors: Department of Immunoregulation, Research Institute for Microbial Diseases, and WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Taroh
authors: T
authors: Kinoshita
authors: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford.
authors: Malcolm F
authors: MF
authors: Howard
authors: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
authors: Monkol
authors: M
authors: Lek
authors: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
authors: Brett
authors: B
authors: Thomas
authors: Department of Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia.
authors: Anne
authors: A
authors: Turner
authors: Western Sydney Genetics Program, Children's Hospital at Westmead, Westmead, NSW, Australia, Discipline of Genetic Medicine, Children's Hospital at Westmead Clinical School, Sydney, NSW, Australia.
authors: John
authors: J
authors: Christodoulou
authors: Western Sydney Genetics Program, Children's Hospital at Westmead, Westmead, NSW, Australia, Discipline of Genetic Medicine, Children's Hospital at Westmead Clinical School, Sydney, NSW, Australia.
authors: David
authors: D
authors: Sillence
authors: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford.
authors: Samantha J L
authors: SJ
authors: Knight
authors: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford.
authors: Niko
authors: N
authors: Popitsch
authors: Institute of Molecular Pathology, Vienna 1030, Austria.
authors: David A
authors: DA
authors: Keays
authors: The Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK.
authors: Consuelo
authors: C
authors: Anzilotti
authors: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors: Anne
authors: A
authors: Goriely
authors: Institute for Neuroscience and Muscle Research, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia.
authors: Leigh B
authors: LB
authors: Waddell
authors: Institute for Neuroscience and Muscle Research, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia.
authors: Fabienne
authors: F
authors: Brilot
authors: Institute for Neuroscience and Muscle Research, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia, Murdoch Children's Research Institute, The Royal Children's Hospital, Flemington Road, Parkville, VIC, Australia and.
authors: Kathryn N
authors: KN
authors: North
authors: Department of Immunoregulation, Research Institute for Microbial Diseases, and WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Noriyuki
authors: N
authors: Kanzawa
authors: Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
authors: Daniel G
authors: DG
authors: Macarthur
authors: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford.
authors: Jenny C
authors: JC
authors: Taylor
authors: Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford OX3 9DU, UK nigel.clarke@health.nsw.gov.au Usha.Kini@ouh.nhs.uk.
authors: Usha
authors: U
authors: Kini
authors: Department of Immunoregulation, Research Institute for Microbial Diseases, and WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors: Yoshiko
authors: Y
authors: Murakami
authors: Institute for Neuroscience and Muscle Research, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia, nigel.clarke@health.nsw.gov.au Usha.Kini@ouh.nhs.uk.
authors: Nigel F
authors: NF
authors: Clarke
mesh_terms: D018958:CD55 Antigens / Q000096:biosynthesis; D018957:CD59 Antigens / Q000096:biosynthesis; D045744:Cell Line, Tumor; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D015870:Gene Expression; D017261:Glycosylphosphatidylinositols / Q000172:deficiency* / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D012640:Seizures; D014162:Transfection
chemical_list: D018958:CD55 Antigens; D018957:CD59 Antigens; D017261:Glycosylphosphatidylinositols; D008565:Membrane Proteins; C507829:PIGY protein, human