Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia

Am J Hum Genet. 2016 Apr 7;98(4):615-26. doi: 10.1016/j.ajhg.2016.02.007.

Periklis Makrythanasis ¹, Mitsuhiro Kato ², Maha S Zaki ³, Hirotomo Saitsu ⁴, Kazuyuki Nakamura ⁵, Federico A Santoni ¹, Satoko Miyatake ⁴, Mitsuko Nakashima ⁴, Mahmoud Y Issa ³, Michel Guipponi ⁶, Audrey Letourneau ⁷, Clare V Logan ⁸, Nicola Roberts ⁸, David A Parry ⁸, Colin A Johnson ⁸, Naomichi Matsumoto ⁴, Hanan Hamamy ⁷, Eamonn Sheridan ⁸, Taroh Kinoshita ⁹, Stylianos E Antonarakis ¹⁰, Yoshiko Murakami ¹¹

Affiliations

1 Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva 1211, Switzerland.
2 Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan; Department of Pediatrics, Showa University School of Medicine, Tokyo 142-8666, Japan.
3 Department of Clinical Genetics, National Research Centre, Cairo 12311, Egypt.
4 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
5 Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan.
6 Service of Genetic Medicine, University Hospitals of Geneva, Geneva 1211, Switzerland.
7 Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland.
8 School of Medicine, University of Leeds, Leeds LS2 9NL, UK.
9 Department of Immunoregulation, Research Institute for Microbial Diseases, and World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
10 Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva 1211, Switzerland; Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva 1211, Switzerland. Electronic address: stylianos.antonarakis@unige.ch.
11 Department of Immunoregulation, Research Institute for Microbial Diseases, and World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan. Electronic address: yoshiko@biken.osaka-u.ac.jp.

PMID: 26996948 DOI: 10.1016/j.ajhg.2016.02.007

Abstract

Glycosylphosphatidylinositol (GPI) is a glycolipid that anchors >150 various proteins to the cell surface. At least 27 genes are involved in biosynthesis and transport of GPI-anchored proteins (GPI-APs). To date, mutations in 13 of these genes are known to cause inherited GPI deficiencies (IGDs), and all are inherited as recessive traits. IGDs mainly manifest as intellectual disability, epilepsy, coarse facial features, and multiple organ anomalies. These symptoms are caused by the decreased surface expression of GPI-APs or by structural abnormalities of GPI. Here, we present five affected individuals (from two consanguineous families from Egypt and Pakistan and one non-consanguineous family from Japan) who show intellectual disability, hypotonia, and early-onset seizures. We identified pathogenic variants in PIGG, a gene in the GPI pathway. In the consanguineous families, homozygous variants c.928C>T (p.Gln310(∗)) and c.2261+1G>C were found, whereas the Japanese individual was compound heterozygous for c.2005C>T (p.Arg669Cys) and a 2.4 Mb deletion involving PIGG. PIGG is the Enzyme that modifies the second mannose with ethanolamine phosphate, which is removed soon after GPI is attached to the protein. Physiological significance of this transient modification has been unclear. Using B lymphoblasts from affected individuals of the Egyptian and Japanese families, we revealed that PIGG activity was almost completely abolished; however, the GPI-APs had normal surface levels and normal structure, indicating that the pathogenesis of PIGG deficiency is not yet fully understood. The discovery of pathogenic variants in PIGG expands the spectrum of IGDs and further enhances our understanding of this etiopathogenic class of intellectual disability.

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