title: Mutations in PIGL in a patient with Mabry syndrome.
abstract: Mabry syndrome, hyperphosphatasia mental retardation syndrome (HPMRS), is an autosomal recessive disease characterized by increased serum levels of alkaline phosphatase (ALP), severe developmental delay, intellectual disability, and seizures. Recent studies have revealed mutations in PIGV, PIGW, PIGO, PGAP2, and PGAP3 (genes that encode molecules of the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway) in patients with HPMRS. We performed whole-exome sequencing of a patient with severe intellectual disability, distinctive facial appearance, fragile nails, and persistent increased serum levels of ALP. The result revealed a compound heterozygote with a 13-bp deletion in exon 1 (c.36_48del) and a two-base deletion in exon 2 (c.254_255del) in phosphatidylinositol glycan anchor, class L (PIGL) that caused frameshifts resulting in premature terminations. The 13-bp deletion was inherited from the father, and the two-base deletion was inherited from the mother. Expressing c.36_48del or c.254_255del cDNA with an HA-tag at the C- or N-terminus in PIGL-deficient CHO cells only partially restored the surface expression of GPI-anchored proteins (GPI-APs). Nonsynonymous changes or frameshift mutations in PIGL have been identified in patients with CHIME syndrome, a rare autosomal recessive disorder characterized by colobomas, congenital heart defects, early onset migratory ichthyosiform dermatosis, intellectual disability, and ear abnormalities. Our patient did not have colobomas, congenital heart defects, or early onset migratory ichthyosiform dermatosis and hence was diagnosed with HPMRS, and not CHIME syndrome. These results suggest that frameshift mutations that result in premature termination in PIGL cause a phenotype that is consistent with HPMRS.
authors.affiliation: Department of Pediatrics, Tohoku University School of Medicine, Sendai, Japan.
authors.forename: Ikuma
authors.initials: I
authors.lastname: Fujiwara
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murakami
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Niihori
authors.forename: Junko
authors.initials: J
authors.lastname: Kanno
authors.forename: Akiko
authors.initials: A
authors.lastname: Hakoda
authors.forename: Osamu
authors.initials: O
authors.lastname: Sakamoto
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.forename: Ryo
authors.initials: R
authors.lastname: Funayama
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagashima
authors.forename: Keiko
authors.initials: K
authors.lastname: Nakayama
authors.forename: Taroh
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Shigeo
authors.initials: S
authors.lastname: Kure
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
authors.forename: Yoko
authors.initials: Y
authors.lastname: Aoki
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002675:Child, Preschool; D006224:Cricetinae; D003412:Cricetulus; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000175:diagnosis* / Q000235:genetics; D008969:Molecular Sequence Data; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D010760:Phosphorus Metabolism Disorders / Q000175:diagnosis* / Q000235:genetics; D017384:Sequence Deletion; D013577:Syndrome
chemical_list: D017351:N-Acetylglucosaminyltransferases; C000603519:PIGL protein, human
keywords: Mabry syndrome; genetic testing; glycosylphosphatidylinositol anchor; hyperphosphatasia mental retardation syndrome