Mild reduction of plasmalogens causes rhizomelic chondrodysplasia punctata: Functional characterization of a novel mutation
Mild reduction of plasmalogens causes rhizomelic chondrodysplasia punctata: Functional characterization of a novel mutation
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缩醛磷脂的轻度减少导致根茎性点状软骨发育不良：新突变的功能特征
DOI：
10.1038/jhg.2014.39
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发表时间：
2014
影响因子：
3.5
通讯作者：
Y.
中科院分区：
文献类型：
--
作者：
Noguchi;M.;Honsho;M.;Abe;Y.;Toyama;R.;Niwa;H.;Sato;Y.;Ghaedi;K.;Rahmanifar;A.;Shafeghati;Y.;and *Fujiki;Y.
斑点状软骨发育不良症(RCDP)是一种常染色体隐性遗传病，因乙醚类脂合成不足所致。RCDP中最突出的一种类型是由针对信号类型2的过氧酶体受体PEX7(Peroxisomal Bigenationfactor7)的功能障碍引起的，其余的RCDP类型2和3型患者在催化烷基磷脂合成的前两步--甘油磷酸O-酰基转移酶和烷基甘油酮磷酸合成酶(AGPS)的过氧化物体酶方面存在缺陷。我们在此调查了两例RCDP 3型患者的缺陷。患者1有一个新的错义突变T1533G，导致AGPS中的I511M替换。AGPS-I511M在成纤维细胞中的蛋白水平和过氧化体定位与对照成纤维细胞一样正常。结构预测分析表明，突变残基位于AGPS V型活性中心隧道表面的螺旋α15上，这可能是血浆蛋白原合成存在轻微缺陷的原因。这些结果强烈地表明，血浆蛋白原合成水平受到轻微影响的个体会患上RCDP。在患者2的成纤维细胞中，AGPS mRNA和AGPS蛋白的表达受到严重影响，从而导致纤溶酶原合成的强烈减少。
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.