title: Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN.
abstract: BACKGROUND
  This study reports on a hitherto undescribed autosomal recessive syndrome characterised by dysmorphic features and multiple congenital anomalies together with severe neurological impairment, chorea and seizures leading to early death, and the identification of a gene involved in the pathogenesis of the disease.
  
  
  METHODS
  Homozygosity mapping was performed using Affymetrix Human Mapping 250k NspI arrays. Sequencing of all coding exons of the candidate genes was performed with primer sets designed using the Primer3 program. Fluorescence activated cell sorting was performed using conjugated antibody to CD59. Staining, acquisition and analysis were performed on a FACSCalibur flow cytometer.
  
  
  RESULTS
  Using homozygosity mapping, the study mapped the disease locus to 18q21.32-18q22.1 and identified the disease-causing mutation, c.2126G→A (p.Arg709Gln), in PIGN, which encodes glycosylphosphatidylinositol (GPI) ethanolamine phosphate transferase 1, a protein involved in GPI-anchor biosynthesis. Arginine at the position 709 is a highly evolutionarily conserved residue located in the PigN domain. The expression of GPI linked protein CD59 on fibroblasts from patients as compared to that in a control individual showed a 10-fold reduction in expression, confirming the pathogenic consequences of the mutation on GPI dependent protein expression.
  
  
  CONCLUSIONS
  The abundant expression of PIGN in various tissues is compatible with the diverse phenotypic features observed in the patients and with the involvement of multiple body systems. The presence of developmental delay, hypotonia, and epilepsy combined with multiple congenital anomalies, especially anorectal anomalies, should lead a clinician to suspect a GPI deficiency related disorder.
authors.affiliation: Department of Internal Medicine D, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.
authors.forename: Gal
authors.initials: G
authors.lastname: Maydan
authors.forename: Iris
authors.initials: I
authors.lastname: Noyman
authors.forename: Adi
authors.initials: A
authors.lastname: Har-Zahav
authors.forename: Ziva Ben
authors.initials: ZB
authors.lastname: Neriah
authors.forename: Metsada
authors.initials: M
authors.lastname: Pasmanik-Chor
authors.forename: Adva
authors.initials: A
authors.lastname: Yeheskel
authors.forename: Adi
authors.initials: A
authors.lastname: Albin-Kaplanski
authors.forename: Idit
authors.initials: I
authors.lastname: Maya
authors.forename: Nurit
authors.initials: N
authors.lastname: Magal
authors.forename: Efrat
authors.initials: E
authors.lastname: Birk
authors.forename: Amos J
authors.initials: AJ
authors.lastname: Simon
authors.forename: Ayelet
authors.initials: A
authors.lastname: Halevy
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Mordechai
authors.initials: M
authors.lastname: Shohat
authors.forename: Rachel
authors.initials: R
authors.lastname: Straussberg
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
mesh_terms: D000015:Abnormalities, Multiple / Q000208:ethnology / Q000235:genetics*; D018912:Arabs / Q000208:ethnology; D001483:Base Sequence; D018957:CD59 Antigens / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D025063:Chromosome Disorders / Q000208:ethnology / Q000235:genetics*; D002874:Chromosome Mapping; D002887:Chromosomes, Human, Pair 18 / Q000737:chemistry*; D003241:Consanguinity; D005091:Exons; D005260:Female; D005434:Flow Cytometry; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006720:Homozygote; D006801:Humans; D007223:Infant; D007557:Israel / Q000453:epidemiology; D019656:Loss of Heterozygosity; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010770:Phosphotransferases / Q000235:genetics*; D016415:Sequence Alignment; D013577:Syndrome; D014166:Transferases / Q000235:genetics*
chemical_list: D018957:CD59 Antigens; D017261:Glycosylphosphatidylinositols; D014166:Transferases; C561296:PIGN protein, human; D010770:Phosphotransferases