Abstract
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.
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Acknowledgments
We thank the patient’s family for participating in this work. We also thank Nobuko Watanabe for her technical assistance. This study was supported by the Ministry of Health, Labour and Welfare of Japan, a Grant-in-Aid for Scientific Research (A), (B), and (C) from the Japan Society for the Promotion of Science, the Takeda Science Foundation, the fund for Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems, the Strategic Research Program for Brain Sciences, and a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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Nakashima, M., Kashii, H., Murakami, Y. et al. Novel compound heterozygous PIGT mutations caused multiple congenital anomalies-hypotonia-seizures syndrome 3. Neurogenetics 15, 193–200 (2014). https://doi.org/10.1007/s10048-014-0408-y
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DOI: https://doi.org/10.1007/s10048-014-0408-y