Phenotype-genotype correlations of PIGO deficiency with variable phenotypes from infantile lethality to mild learning difficulties.
Inherited GPI (glycosylphosphatidylinositol) deficiencies (IGDs), a recently defined group of diseases, show a broad spectrum of symptoms. Hyperphosphatasia mental retardation syndrome, also known as Mabry syndrome, is a type of IGDs. There are at least 26 genes involved in the biosynthesis and transport of GPI-anchored proteins; however, IGDs constitute a rare group of diseases, and correlations between the spectrum of symptoms and affected genes or the type of mutations have not been shown. Here, we report four newly identified and five previously described Japanese families with PIGO (phosphatidylinositol glycan anchor biosynthesis class O) deficiency. We show how the clinical severity of IGDs correlates with flow cytometric analysis of blood, functional analysis using a PIGO-deficient cell line, and the degree of hyperphosphatasia. The flow cytometric analysis and hyperphosphatasia are useful for IGD diagnosis, but the expression level of GPI-anchored proteins and the degree of hyperphosphatasia do not correlate, although functional studies do, with clinical severity. Compared with PIGA (phosphatidylinositol glycan anchor biosynthesis class A) deficiency, PIGO deficiency shows characteristic features, such as Hirschsprung disease, brachytelephalangy, and hyperphosphatasia. This report shows the precise spectrum of symptoms according to the severity of mutations and compares symptoms between different types of IGD.
Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Junpei
J
Tanigawa
Division of Neonatology Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Aichi, Japan.
Haruka
H
Mimatsu
Department of Pediatrics, Central Hospital, Aichi Human Service Center, Kasugai, Aichi, Japan.
Seiji
S
Mizuno
Department of Medical Genetics, Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan.
Nobuhiko
N
Okamoto
Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
Daisuke
D
Fukushi
Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.|Department of Child Development, United Graduate School of Child Development, Osaka University, Suita, Osaka, Japan.
Koji
K
Tominaga
Department of Pediatrics, Nagoya University Hospital, Nagoya, Aichi, Japan.
Hiroyuki
H
Kidokoro
Division of Neonatology Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Aichi, Japan.
Yukako
Y
Muramatsu
Department of Pediatrics, Central Hospital, Aichi Human Service Center, Kasugai, Aichi, Japan.
Eriko
E
Nishi
Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
Shota
S
Nakamura
Department of Infection Metagenomics, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
Daisuke
D
Motooka
Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
Noriko
N
Nomura
Department of Pediatrics, Yamagata University School of Medicine, Yamagata, Yamagata, Japan.
Kiyoshi
K
Hayasaka
Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Miyagi, Japan.
Tetsuya
T
Niihori
Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Miyagi, Japan.
Yoko
Y
Aoki
Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Shin
S
Nabatame
Division of Neonatology Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Aichi, Japan.
Masahiro
M
Hayakawa
Department of Developmental Disability Medicine and Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Jun
J
Natsume
Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Keiichi
K
Ozono
Department of Immunoregulation, Research Institute for Microbial Diseases Osaka University, Suita, Osaka, Japan.
Taroh
T
Kinoshita
Department of Genetics, Institute for Developmental Research, Aichi Human Service Center, Kasugai, Aichi, Japan.
Nobuaki
N
Wakamatsu
Department of Immunoregulation, Research Institute for Microbial Diseases Osaka University, Suita, Osaka, Japan.
Yoshiko
Y
Murakami
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D007564:Japan; D007859:Learning Disabilities / Q000235:genetics* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D013577:Syndrome
D008565:Membrane Proteins; C485854:PIGO protein, human; C080086:phosphatidylinositol glycan-class A protein
Hirschsprung disease; PIGO; epilepsy; glycosylphosphatidylinositol (GPI); inherited glycosylphosphatidylinositol deficiency (IGD)