Mild reduction of plasmalogens causes rhizomelic chondrodysplasia punctata: Functional characterization of a novel mutation

Masafumi Noguchi, Masanori Honsho, Yuichi Abe, Ryusuke Toyama, Hajime Niwa, Yoshiteru Sato, Kamran Ghaedi, Ali Rahmanifar, Yousef Shafeghati, Yukio Fujiki

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive disorder due to the deficiency in ether lipid synthesis. RCDP type 1, the most prominent type, is caused by the dysfunction of the receptor of peroxisome targeting signal type 2, Pex7 (peroxisomal biogenesis factor 7), and the rest of the patients, RCDP types 2 and 3, have defects in peroxisomal enzymes catalyzing the initial two steps of alkyl-phospholipid synthesis, glyceronephosphate O-acyltransferase and alkylglycerone phosphate synthase (Agps). We herein investigated defects of two patients with RCDP type 3. Patient 1 had a novel missense mutation, T1533G, resulting in the I511M substitution in Agps. The plasmalogen level was mildly reduced, whereas the protein level and peroxisomal localization of Agps-I511M in fibroblasts were normal as in the control fibroblasts. Structure prediction analysis suggested that the mutated residue was located in the helix α15 on the surface of V-shaped active site tunnel in Agps, likely accounting for the mild defects of plasmalogen synthesis. These results strongly suggest that an individual with mildly affected level of plasmalogen synthesis develops RCDP. In fibroblasts from patient 2, the expression of AGPS mRNA and Agps protein was severely affected, thereby giving rise to the strong reduction of plasmalogen synthesis.

Original languageEnglish
Pages (from-to)387-392
Number of pages6
JournalJournal of Human Genetics
Volume59
Issue number7
DOIs
Publication statusPublished - Jul 2014

All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

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