%0 Journal Article
%T Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy
%A Alejandro D. Iglesias
%A Angela E. Scheuerle
%A Anik St-Denis
%A Denise L. Perry
%A Diane Masser-Frye
%A Fran£¿oise Le Deist
%A Jill A. Rosenfeld
%A Julie Jones
%A Justine Rousseau
%A Kristen M. Wigby
%A Marilyn C. Jones
%A Miles Thompson
%A Nissan V. Baratang
%A Ryan J. Taft
%A Stephanie C. Laniewski
%A Taroh Kinoshita
%A Thi Tuyet Mai Nguyen
%A Yoshiko Murakami
%J Archive of "American Journal of Human Genetics".
%D 2018
%R 10.1016/j.ajhg.2018.08.014
%X Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result of advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS). IGDs cause a series of overlapping phenotypes consisting of seizures, dysmorphic features, multiple congenital malformations, and severe intellectual disability. We present a study of six individuals from three unrelated families in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations. Phenotypes included severe global developmental delay, seizures (partly responding to pyridoxine), hypotonia, weakness, ataxia, and dysmorphic facial features. Two of them had compound-heterozygous variants c.108G>A (p.Trp36£¿) and c.101T>C (p.Leu34Pro), and two siblings of another family were homozygous for a deletion and insertion leading to p.Thr439_Lys451delinsArgLeuLeu. The third family had two fetuses with multiple joint contractures consistent with fetal akinesia. They were compound heterozygous for c.923A>G (p.Glu308Gly) and c.468+1G>C, a splicing mutation. Flow-cytometry analyses demonstrated that the individuals with PIGS mutations show a GPI-AP deficiency profile. Expression of the p.Trp36£¿ variant in PIGS-deficient HEK293 cells revealed only partial restoration of cell-surface GPI-APs. In terms of both biochemistry and phenotype, loss of function of PIGS shares features with PIGT deficiency and other IGDs. This study contributes to the understanding of the GPI-AP biosynthesis pathway by describing the consequences of PIGS disruption in humans and extending the family of IGDs
%K PIGS
%K glycosylphosphatidylinositol
%K epilepsy
%K seizures
%K inherited GPI deficiency
%K glycosylphosphatidylinositol biosynthesis defect
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6174287/