2. Academic Validation
  3. Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies

Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies

  • Hum Mol Genet. 2015 Nov 1;24(21):6146-59. doi: 10.1093/hmg/ddv331.
Biljana Ilkovski 1,  Alistair T Pagnamenta 2,  Gina L O'Grady 3,  Taroh Kinoshita 4,  Malcolm F Howard 2,  Monkol Lek 5,  Brett Thomas 5,  Anne Turner 6,  John Christodoulou 7,  David Sillence 7,  Samantha J L Knight 2,  Niko Popitsch 2,  David A Keays 8,  Consuelo Anzilotti 9,  Anne Goriely 10,  Leigh B Waddell 3,  Fabienne Brilot 3,  Kathryn N North 11,  Noriyuki Kanzawa 4,  Daniel G Macarthur 5,  Jenny C Taylor 2,  Usha Kini 12,  Yoshiko Murakami 4,  Nigel F Clarke 13
Affiliations

Affiliations

  • 1 Institute for Neuroscience and Muscle Research.
  • 2 National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford.
  • 3 Institute for Neuroscience and Muscle Research, Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW, Australia.
  • 4 Department of Immunoregulation, Research Institute for Microbial Diseases, and WPI Immunology Frontier Research Center, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan.
  • 5 Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA, USA.
  • 6 Department of Clinical Genetics, Sydney Children's Hospital, Sydney, NSW, Australia.
  • 7 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.
  • 8 Institute of Molecular Pathology, Vienna 1030, Austria.
  • 9 The Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford OX3 7BN, UK.
  • 10 Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • 11 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.
  • 12 Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford OX3 9DU, UK nigel.clarke@health.nsw.gov.au Usha.Kini@ouh.nhs.uk.
  • 13 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.
PMID: 26293662 DOI: 10.1093/hmg/ddv331
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.

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