Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy

Thi Tuyet Mai Nguyen, Yoshiko Murakami, Kristen M. Wigby, Nissan V. Baratang, Justine Rousseau, Anik St-Denis, Jill A. Rosenfeld, Stephanie C. Laniewski, Julie Jones, Alejandro D. Iglesias, Marilyn C. Jones, Diane Masser-Frye, Angela E. Scheuerle, Denise L. Perry, Ryan J. Taft, Françoise Le Deist, Miles Thompson, Taroh Kinoshita, Philippe M. Campeau

Research output: Contribution to journalArticle

9 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)602-611
Number of pages10
JournalAmerican Journal of Human Genetics
Volume103
Issue number4
DOIs
StatePublished - Oct 4 2018

Keywords

  • PIGS
  • epilepsy
  • glycosylphosphatidylinositol
  • glycosylphosphatidylinositol biosynthesis defect
  • inherited GPI deficiency
  • seizures

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Nguyen, T. T. M., Murakami, Y., Wigby, K. M., Baratang, N. V., Rousseau, J., St-Denis, A., Rosenfeld, J. A., Laniewski, S. C., Jones, J., Iglesias, A. D., Jones, M. C., Masser-Frye, D., Scheuerle, A. E., Perry, D. L., Taft, R. J., Le Deist, F., Thompson, M., Kinoshita, T., & Campeau, P. M. (2018). Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy. American Journal of Human Genetics, 103(4), 602-611. https://doi.org/10.1016/j.ajhg.2018.08.014