Mild reduction of plasmalogens causes rhizomelic chondrodysplasia punctata: functional characterization of a novel mutation.
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.
Graduate School of Systems Life Sciences, Kyushu University Graduate School, Higashi-ku, Fukuoka, Japan.
Masafumi
M
Noguchi
Department of Biology, Faculty of Sciences, Kyushu University Graduate School, Higashi-ku, Fukuoka, Japan.
Masanori
M
Honsho
Department of Biology, Faculty of Sciences, Kyushu University Graduate School, Higashi-ku, Fukuoka, Japan.
Yuichi
Y
Abe
Department of Biology, Faculty of Sciences, Kyushu University Graduate School, Higashi-ku, Fukuoka, Japan.
Ryusuke
R
Toyama
Department of Biology, Faculty of Sciences, Kyushu University Graduate School, Higashi-ku, Fukuoka, Japan.
Hajime
H
Niwa
Department of Biology, Faculty of Sciences, Kyushu University Graduate School, Higashi-ku, Fukuoka, Japan.
Yoshiteru
Y
Sato
Department of Biology, School of Sciences, University of Isfahan, and Cell Sciences Research Center, Royan Institute, Isfahan Research Station, Isfahan, Iran.
Kamran
K
Ghaedi
Medical Genetic Metabolic Center, Sarem Women Hospital, Tehran, Iran.
Ali
A
Rahmanifar
Sarem Cell Research Center and Medical Genetics Department and Genetics Research Center, University of Social Welfare Sciences and Rehabilitation, Tehran, Iran.
Yousef
Y
Shafeghati
Department of Biology, Faculty of Sciences, Kyushu University Graduate School, Higashi-ku, Fukuoka, Japan.
Yukio
Y
Fujiki
D019883:Alkyl and Aryl Transferases / Q000737:chemistry / Q000235:genetics*; D002460:Cell Line; D002675:Child, Preschool; D018902:Chondrodysplasia Punctata, Rhizomelic / Q000235:genetics* / Q000378:metabolism*; D004252:DNA Mutational Analysis; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D010955:Plasmalogens / Q000378:metabolism*; D011487:Protein Conformation; D012333:RNA, Messenger / Q000235:genetics
D010955:Plasmalogens; D012333:RNA, Messenger; D019883:Alkyl and Aryl Transferases; C019654:alkylglycerone-phosphate synthase