RT Journal Article
SR Electronic
T1 Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in <em>PIGN</em>
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 383
OP 389
DO 10.1136/jmg.2010.087114
VO 48
IS 6
A1 Maydan, Gal
A1 Noyman, Iris
A1 Har-Zahav, Adi
A1 Neriah, Ziva Ben
A1 Pasmanik-Chor, Metsada
A1 Yeheskel, Adva
A1 Albin-Kaplanski, Adi
A1 Maya, Idit
A1 Magal, Nurit
A1 Birk, Efrat
A1 Simon, Amos J
A1 Halevy, Ayelet
A1 Rechavi, Gideon
A1 Shohat, Mordechai
A1 Straussberg, Rachel
A1 Basel-Vanagaite, Lina
YR 2011
UL http://jmg.bmj.com/content/48/6/383.abstract
AB 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.