Document Detail

Defective lipid remodeling of GPI anchors in peroxisomal disorders, Zellweger syndrome, and rhizomelic chondrodysplasia punctata.
MedLine Citation:
PMID:  22253471     Owner:  NLM     Status:  MEDLINE    
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.
Noriyuki Kanzawa; Nobuyuki Shimozawa; Ronald J A Wanders; Kazutaka Ikeda; Yoshiko Murakami; Hans R Waterham; Satoru Mukai; Morihisa Fujita; Yusuke Maeda; Ryo Taguchi; Yukio Fujiki; Taroh Kinoshita
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-01-17
Journal Detail:
Title:  Journal of lipid research     Volume:  53     ISSN:  0022-2275     ISO Abbreviation:  J. Lipid Res.     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-03-13     Completed Date:  2012-07-02     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0376606     Medline TA:  J Lipid Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  653-63     Citation Subset:  IM    
Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Acyltransferases / genetics,  metabolism
Alkyl and Aryl Transferases / genetics,  metabolism
CHO Cells
Cell Line, Transformed
Chondrodysplasia Punctata, Rhizomelic / genetics,  metabolism,  pathology*
Fibroblasts / metabolism,  pathology
Glycosylphosphatidylinositols / metabolism*
Membrane Proteins / genetics,  metabolism
Peroxisomes / genetics,  metabolism
Receptors, Cytoplasmic and Nuclear / genetics,  metabolism
Zellweger Syndrome / genetics,  metabolism,  pathology*
Reg. No./Substance:
0/Glycosylphosphatidylinositols; 0/Membrane Proteins; 0/PEX16 protein, human; 0/Receptors, Cytoplasmic and Nuclear; 0/peroxisomal targeting signal 2 receptor; 157153-79-2/PEX19 protein, human; EC 2.3.-/Acyltransferases; EC O-acyltransferase; EC 2.5.-/Alkyl and Aryl Transferases; EC synthase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Recommendations for clinical trials of off-label drugs used to treat advanced-stage cancer.
Next Document:  MicroRNAs control neurobehavioral development and function in zebrafish.