Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3

Brandon Itzkovitz, Sarn Jiralerspong, Graeme Nimmo, Melissa Loscalzo, Dafne D.G. Horovitz, Ann Snowden, Ann Moser, Steve Steinberg, Nancy Braverman

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)189-197
Number of pages9
JournalHuman mutation
Volume33
Issue number1
DOIs
StatePublished - Jan 2012

Keywords

  • AGPS
  • GNPAT
  • Peroxisome disease
  • Plasmalogen
  • RCDP

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Fingerprint

Dive into the research topics of 'Functional characterization of novel mutations in GNPAT and AGPS, causing rhizomelic chondrodysplasia punctata (RCDP) types 2 and 3'. Together they form a unique fingerprint.

Cite this