title: A novel intellectual disability syndrome caused by GPI anchor deficiency due to homozygous mutations in PIGT.
abstract: OBJECTIVE
  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.
authors: Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. malin.kvarnung@karolinska.se
authors: Malin
authors: M
authors: Kvarnung
authors: Daniel
authors: D
authors: Nilsson
authors: Anna
authors: A
authors: Lindstrand
authors: G Christoph
authors: GC
authors: Korenke
authors: Samuel C C
authors: SC
authors: Chiang
authors: Elisabeth
authors: E
authors: Blennow
authors: Markus
authors: M
authors: Bergmann
authors: Tommy
authors: T
authors: Stödberg
authors: Outi
authors: O
authors: Mäkitie
authors: Britt-Marie
authors: BM
authors: Anderlid
authors: Yenan T
authors: YT
authors: Bryceson
authors: Magnus
authors: M
authors: Nordenskjöld
authors: Ann
authors: A
authors: Nordgren
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002675:Child, Preschool; D003241:Consanguinity; D004625:Embryo, Nonmammalian / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D017261:Glycosylphosphatidylinositols / Q000172:deficiency* / Q000235:genetics*; D006457:Hemoglobinuria, Paroxysmal / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D012640:Seizures / Q000235:genetics*; D013577:Syndrome; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism
chemical_list: D017261:Glycosylphosphatidylinositols
keywords: Clinical genetics; Developmental; Epilepsy and seizures; Genetic screening/counselling; Molecular genetics