title: Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3.
abstract: Rhizomelic chondrodysplasia punctata (RCDP) is a disorder of peroxisome metabolism resulting from a deficiency of plasmalogens, a specialized class of membrane phospholipids. Classically, patients have a skeletal dysplasia and profound mental retardation, although milder phenotypes are increasingly being identified. It is commonly caused by defects in the peroxisome transporter, PEX7 (RCDP1), and less frequently due to defects in the peroxisomal enzymes required to initiate plasmalogen synthesis, GNPAT (RCDP2) and AGPS (RCDP3). PEX7 transports AGPS into the peroxisome, where AGPS and GNPAT partner on the luminal membrane surface. The presence of AGPS is thought to be required for GNPAT activity. We present six additional probands with RCDP2 and RCDP3, and the novel mutations identified in them. Using cell lines from these and previously reported patients, we compared the amounts of both AGPS and GNPAT proteins present for the first time. We used protein modeling to predict the structural consequences of AGPS mutations and transcript analysis to predict consequences of GNPAT mutations, and show that milder RCDP phenotypes are likely to be associated with residual protein function. In addition, we propose that full GNPAT activity depends not only on the presence of AGPS, but also on the integrity of substrate channeling from GNPAT to AGPS.
authors: Montreal Children's Hospital Research Institute, Montreal, Quebec, Canada.
authors: Brandon
authors: B
authors: Itzkovitz
authors: Sarn
authors: S
authors: Jiralerspong
authors: Graeme
authors: G
authors: Nimmo
authors: Melissa
authors: M
authors: Loscalzo
authors: Dafne D G
authors: DD
authors: Horovitz
authors: Ann
authors: A
authors: Snowden
authors: Ann
authors: A
authors: Moser
authors: Steve
authors: S
authors: Steinberg
authors: Nancy
authors: N
authors: Braverman
mesh_terms: D000217:Acyltransferases / Q000235:genetics* / Q000378:metabolism; D019883:Alkyl and Aryl Transferases / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D018902:Chondrodysplasia Punctata, Rhizomelic / Q000201:enzymology / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D020675:Peroxisomes / Q000235:genetics / Q000378:metabolism; D010955:Plasmalogens / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D012720:Severity of Illness Index
chemical_list: D010955:Plasmalogens; D012333:RNA, Messenger; D000217:Acyltransferases; C020051:glycerone-phosphate O-acyltransferase; D019883:Alkyl and Aryl Transferases; C019654:alkylglycerone-phosphate synthase