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.