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J Med Genet doi:10.1136/jmedgenet-2013-101654
  • New loci
  • Original Article

A novel intellectual disability syndrome caused by GPI anchor deficiency due to homozygous mutations in PIGT

  1. Ann Nordgren1,2,3
  1. 1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
  2. 2Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
  3. 3Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
  4. 4Science for Life Laboratory, Karolinska Institutet Science Park, Stockholm, Sweden
  5. 5Department of Neuropediatrics, Children's Hospital, Klinikum Oldenburg, Oldenburg, Germany
  6. 6Department of Medicine, Centre for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden
  7. 7Institute for Neuropathology, Klinikum Bremen-Mitte, Bremen, Germany
  8. 8Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
  9. 9Department of Child Neurology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm
  10. 10Children's Hospital, Helsinki University Central Hospital, University of Helsinki, and Folkhälsan Institute of Genetics, Helsinki, Finland
  1. Correspondence to Dr Malin Kvarnung and Ann Nordgren, Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm 17176, Sweden; malin.kvarnung{at}karolinska.se, ann.nordgren{at}ki.se
  • Received 12 March 2013
  • Revised 11 April 2013
  • Accepted 12 April 2013
  • Published Online First 1 May 2013

Abstract

Purpose To delineate the molecular basis for a novel autosomal recessive syndrome, characterised by distinct facial features, intellectual disability, hypotonia and seizures, in combination with abnormal skeletal, endocrine, and ophthalmologic findings.

Methods We examined four patients from a consanguineous kindred with a strikingly similar phenotype, by using whole exome sequencing (WES). Functional validation of the initial results were performed by flow cytometry determining surface expression of glycosylphosphatidylinositol (GPI) and GPI anchored proteins and, in addition, by in vivo assays on zebrafish embryos.

Results The results from WES identified a homozygous mutation, c.547A>C (p.Thr183Pro), in PIGT; Sanger sequencing of additional family members confirmed segregation with the disease. PIGT encodes phosphatidylinositol-glycan biosynthesis class T (PIG-T) protein, which is a subunit of the transamidase complex that catalyses the attachment of proteins to GPI. By flow cytometry, we found that granulocytes from the patients had reduced levels of the GPI anchored protein CD16b, supporting pathogenicity of the mutation. Further functional in vivo validation via morpholino mediated knockdown of the PIGT ortholog in zebrafish (pigt) showed that, unlike human wild-type PIGT mRNA, the p.Thr183Pro encoding mRNA failed to rescue gastrulation defects induced by the suppression of pigt.

Conclusions We identified mutations in PIGT as the cause of a novel autosomal recessive intellectual disability syndrome. Our results demonstrate a new pathogenic mechanism in the GPI anchor pathway and expand the clinical spectrum of disorders belonging to the group of GPI anchor deficiencies.

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