TY - JOUR
T1 - Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy
AU - Nguyen, Thi Tuyet Mai
AU - Murakami, Yoshiko
AU - Wigby, Kristen M.
AU - Baratang, Nissan V.
AU - Rousseau, Justine
AU - St-Denis, Anik
AU - Rosenfeld, Jill A.
AU - Laniewski, Stephanie C.
AU - Jones, Julie
AU - Iglesias, Alejandro D.
AU - Jones, Marilyn C.
AU - Masser-Frye, Diane
AU - Scheuerle, Angela E.
AU - Perry, Denise L.
AU - Taft, Ryan J.
AU - Le Deist, Françoise
AU - Thompson, Miles
AU - Kinoshita, Taroh
AU - Campeau, Philippe M.
N1 - Publisher Copyright:
© 2018 American Society of Human Genetics
PY - 2018/10/4
Y1 - 2018/10/4
N2 - 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.
AB - 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.
KW - PIGS
KW - epilepsy
KW - glycosylphosphatidylinositol
KW - glycosylphosphatidylinositol biosynthesis defect
KW - inherited GPI deficiency
KW - seizures
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U2 - 10.1016/j.ajhg.2018.08.014
DO - 10.1016/j.ajhg.2018.08.014
M3 - Article
C2 - 30269814
AN - SCOPUS:85054423529
SN - 0002-9297
VL - 103
SP - 602
EP - 611
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 4
ER -