Novel compound heterozygous PIGT mutations caused multiple congenital anomalies-hypotonia-seizures syndrome 3

• DOI: 10.1007/s10048-014-0408-y
• Publication Date: 2014-06-10T18:09:22Z
• Authors: Mitsuko Nakashima; Hirofumi Kashii; Yoshiko Murakami; Mitsuhiro Kato; Yoshinori Tsurusaki; Noriko Miyake; Masaya Kubota; Taroh Kinoshita; Hirotomo Saitsu; Naomichi Matsumoto
• Keywords: Compound heterozygosity; Heterozygote advantage; Human genetics

Recessive mutations in genes of the glycosylphosphatidylinositol (GPI)-anchor synthesis pathway have been demonstrated as causative of GPI deficiency disorders associated with intellectual disability, seizures, and diverse congenital anomalies. We performed whole exome sequencing in a patient with progressive encephalopathies and multiple dysmorphism with hypophosphatasia and identified novel compound heterozygous mutations, c.250G>T (p. Glu84*) and c.1342C>T (p. Arg488Trp), in PIGT encoding a subunit of the GPI transamidase complex. The surface expression of GPI-anchored proteins (GPI-APs) on patient granulocytes was lower than that of healthy controls. Transfection of the Arg488Trp mutant PIGT construct, but not the Glu84* mutant, into PIGT-deficient cells partially restored the expression of GPI-APs DAF and CD59. These results indicate that PIGT mutations caused neurological impairment and multiple congenital anomalies in this patient.