Identification of a novel PEX14 mutation in Zellweger syndrome
Identification of a novel PEX14 mutation in Zellweger syndrome
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DOI：
10.1136/jmg.2007.056697
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发表时间：
2008-06-01
影响因子：
4
通讯作者：
Cassiman, D.
中科院分区：
文献类型：
--
作者：
Huybrechts, S. J.;Van Veldhoven, P. P.;Cassiman, D.
背景资料：过氧化物酶体生物合成障碍是一组临床和遗传异质性非常严重的常染色体隐性遗传疾病，由受损的过氧化物酶体生物合成引起。这组疾病的原型是肝-肾综合征的Zellweger.Methods和结果：在这里，我们报告一个病人与Zellweger综合征，谁在3个月的年龄与黄疸，营养不良，轴向肌张力减退，面部畸形，后胚胎毒素，和肝肿大。代谢筛查试验的异常发现包括高胆红素血症、低酮二羧酸尿、C-26：0血浆水平升高和C-22：0血浆水平降低以及血浆原浓度大幅降低。在成纤维细胞中，过氧化物酶体α-和β-氧化均受损。肝脏组织学显示胆管缺乏、胆汁淤积、动脉增生、门静脉分支非常小和实质破坏。培养的成纤维细胞的免疫细胞化学分析表明，细胞含有过氧化物酶体残留物缺乏明显的基质蛋白含量和PEX 14，过氧化物酶体基质蛋白进口机械的中央膜组件。用编码野生型PEX 14的质粒转染成纤维细胞恢复了过氧化物酶体基质蛋白的输入，表明影响患者的主要遗传缺陷确实与PEX 14有关。该基因的突变分析揭示了基因组缺失，导致编码DNA中外显子3的缺失（c.85-？_一百七十多？del）和伴随的阅读框架的变化（p. [Ile29_Lys56del;结论：该报告代表了与Zellweger综合征相关的第二种PEX 14缺陷，并且首次记录了具有详细临床随访和生化、形态学和放射学数据的PEX 14缺陷患者。
Background: Peroxisome biogenesis disorders are a clinically and genetically heterogeneous group of very severe autosomal recessive disorders caused by impaired peroxisome biogenesis. The prototype of this group of disorders is the cerebro-hepato-renal syndrome of Zellweger.Methods and results: Here we report a patient with Zellweger syndrome, who presented at the age of 3 months with icterus, dystrophy, axial hypotonia, facial dysmorphy, posterior embryotoxon, and hepatomegaly. Abnormal findings of metabolic screening tests included hyperbilirubinaemia, hypoketotic dicarboxylic aciduria, increased C-26:0 and decreased C-22:0 plasma levels, and strongly reduced plasmalogen concentrations. In fibroblasts, both peroxisomal alpha- and beta-oxidation were impaired. Liver histology revealed bile duct paucity, cholestasis, arterial hyperplasia, very small branches of the vena portae, and parenchymatic destruction. Immunocytochemical analysis of cultured fibroblasts demonstrated that the cells contain peroxisomal remnants lacking apparent matrix protein content and PEX14, a central membrane component of the peroxisomal matrix protein import machinery. Transfection of fibroblasts with a plasmid coding for wild-type PEX14 restored peroxisomal matrix protein import, indicating that the primary genetic defect affecting the patient is indeed linked to PEX14. Mutational analysis of this gene revealed a genomic deletion leading to the deletion of exon 3 from the coding DNA (c.85-?_170+?del) and a concomitant change of the reading frame (p.[Ile29_Lys56del; Gly57GlyfsX2]).Conclusions: This report represents the second PEX14-deficiency associated with Zellweger syndrome and the first documentation of a PEX14-deficient patient with detailed clinical follow-up and biochemical, morphological, and radiological data.