title: Defective lipid remodeling of GPI anchors in peroxisomal disorders, Zellweger syndrome, and rhizomelic chondrodysplasia punctata.
abstract: Many cell surface proteins in mammalian cells are anchored to the plasma membrane via glycosylphosphatidylinositol (GPI). The predominant form of mammalian GPI contains 1-alkyl-2-acyl phosphatidylinositol (PI), which is generated by lipid remodeling from diacyl PI. The conversion of diacyl PI to 1-alkyl-2-acyl PI occurs in the ER at the third intermediate in the GPI biosynthetic pathway. This lipid remodeling requires the alkyl-phospholipid biosynthetic pathway in peroxisome. Indeed, cells defective in dihydroxyacetone phosphate acyltransferase (DHAP-AT) or alkyl-DHAP synthase express only the diacyl form of GPI-anchored proteins. A defect in the alkyl-phospholipid biosynthetic pathway causes a peroxisomal disorder, rhizomelic chondrodysplasia punctata (RCDP), and defective biogenesis of peroxisomes causes Zellweger syndrome, both of which are lethal genetic diseases with multiple clinical phenotypes such as psychomotor defects, mental retardation, and skeletal abnormalities. Here, we report that GPI lipid remodeling is defective in cells from patients with Zellweger syndrome having mutations in the peroxisomal biogenesis factors PEX5, PEX16, and PEX19 and in cells from patients with RCDP types 1, 2, and 3 caused by mutations in PEX7, DHAP-AT, and alkyl-DHAP synthase, respectively. Absence of the 1-alkyl-2-acyl form of GPI-anchored proteins might account for some of the complex phenotypes of these two major peroxisomal disorders.
authors.affiliation: Department of Immunoregulation, Research Institute for Microbial Diseases,  Osaka University, Suita, Osaka 565-0871,  Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kanzawa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Shimozawa
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ikeda
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murakami
authors.forename: Hans R
authors.initials: HR
authors.lastname: Waterham
authors.forename: Satoru
authors.initials: S
authors.lastname: Mukai
authors.forename: Morihisa
authors.initials: M
authors.lastname: Fujita
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Maeda
authors.forename: Ryo
authors.initials: R
authors.lastname: Taguchi
authors.forename: Yukio
authors.initials: Y
authors.lastname: Fujiki
authors.forename: Taroh
authors.initials: T
authors.lastname: Kinoshita
mesh_terms: D000217:Acyltransferases / Q000235:genetics / Q000378:metabolism; D019883:Alkyl and Aryl Transferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D002461:Cell Line, Transformed; D018902:Chondrodysplasia Punctata, Rhizomelic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006224:Cricetinae; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D000074437:Peroxisomal Targeting Signal 2 Receptor; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D015211:Zellweger Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D017261:Glycosylphosphatidylinositols; D008565:Membrane Proteins; C486345:PEX16 protein, human; C000614269:PEX7 protein, human; D000074437:Peroxisomal Targeting Signal 2 Receptor; D018160:Receptors, Cytoplasmic and Nuclear; C087343:PEX19 protein, human; D000217:Acyltransferases; C020051:glycerone-phosphate O-acyltransferase; D019883:Alkyl and Aryl Transferases; C019654:alkylglycerone-phosphate synthase