title: Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia.
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.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva 1211, Switzerland.
authors.forename: Periklis
authors.initials: P
authors.lastname: Makrythanasis
authors.affiliation: Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan; Department of Pediatrics, Showa University School of Medicine, Tokyo 142-8666, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Clinical Genetics, National Research Centre, Cairo 12311, Egypt.
authors.forename: Maha S
authors.initials: MS
authors.lastname: Zaki
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.affiliation: Department of Pediatrics, Yamagata University Faculty of Medicine, Yamagata 990-9585, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland; Service of Genetic Medicine, University Hospitals of Geneva, Geneva 1211, Switzerland.
authors.forename: Federico A
authors.initials: FA
authors.lastname: Santoni
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.affiliation: Department of Clinical Genetics, National Research Centre, Cairo 12311, Egypt.
authors.forename: Mahmoud Y
authors.initials: MY
authors.lastname: Issa
authors.affiliation: Service of Genetic Medicine, University Hospitals of Geneva, Geneva 1211, Switzerland.
authors.forename: Michel
authors.initials: M
authors.lastname: Guipponi
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland.
authors.forename: Audrey
authors.initials: A
authors.lastname: Letourneau
authors.affiliation: School of Medicine, University of Leeds, Leeds LS2 9NL, UK.
authors.forename: Clare V
authors.initials: CV
authors.lastname: Logan
authors.affiliation: School of Medicine, University of Leeds, Leeds LS2 9NL, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Roberts
authors.affiliation: School of Medicine, University of Leeds, Leeds LS2 9NL, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Parry
authors.affiliation: School of Medicine, University of Leeds, Leeds LS2 9NL, UK.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland.
authors.forename: Hanan
authors.initials: H
authors.lastname: Hamamy
authors.affiliation: School of Medicine, University of Leeds, Leeds LS2 9NL, UK.
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.affiliation: Department of Immunoregulation, Research Institute for Microbial Diseases, and World Premier International Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan.
authors.forename: Taroh
authors.initials: T
authors.lastname: Kinoshita
authors.affiliation: 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.
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.affiliation: 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.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murakami
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000293:Adolescent; D045744:Cell Line, Tumor; D002648:Child; D003241:Consanguinity; D004534:Egypt; D014644:Genetic Variation; D060005:Genotyping Techniques; D017261:Glycosylphosphatidylinositols / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics*; D007564:Japan; D008364:Mannosyltransferases / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics*; D009154:Mutation; D010154:Pakistan; D010375:Pedigree; D012640:Seizures / Q000235:genetics*; D055815:Young Adult
chemical_list: D017261:Glycosylphosphatidylinositols; D008364:Mannosyltransferases