A novel defect of peroxisome division due to a homozygous non-sense mutation in the PEX11β gene
A novel defect of peroxisome division due to a homozygous non-sense mutation in the PEX11β gene
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DOI：
10.1136/jmedgenet-2012-100778
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发表时间：
2012-05-01
影响因子：
4
通讯作者：
Waterham, Hans R.
中科院分区：
文献类型：
--
作者：
Ebberink, Merel S.;Koster, Janet;Waterham, Hans R.
背景过氧化物酶体是一种不断增殖的细胞器，在人体代谢中起着不可或缺的作用。因此，过氧化物酶体基因缺陷可导致多种通常严重的疾病，包括过氧化物酶体生物发生障碍。目前，有13种不同的PEX蛋白参与了过氧化物酶体组装和蛋白质输入的各个阶段。任何这些蛋白质的缺陷都会导致过氧化物酶体生物合成障碍。作者在此提出了一种新的遗传缺陷，特别是影响过氧化物酶体的分裂。方法作者研究了培养的患者成纤维细胞的生化和显微镜过氧化物酶体参数，对候选PEX基因进行测序，并确定了在不同温度下鉴定的PEX 11 β基因缺陷对患者成纤维细胞过氧化物酶体生物合成的影响。结果该患者表现为先天性白内障，轻度智力残疾，进行性听力损失、感觉神经受累、胃肠道问题和复发性偏头痛样发作。虽然患者成纤维细胞的显微镜检查表明过氧化物酶体分裂有明显缺陷，但通常用于诊断过氧化物酶体疾病的所有生化参数均正常。在排除了先前与过氧化物酶体生物合成障碍有关的所有PEX基因突变后，发现该缺陷是由PEX11 β基因中的纯合无义突变引起的。过氧化物酶体分裂缺陷加剧时，患者的成纤维细胞培养在40摄氏度，这与PEX11 γ的表达显着下降。结论这种新的孤立的缺陷过氧化物酶体分裂扩大了临床和遗传谱的过氧化物酶体疾病，并表明过氧化物酶体缺陷的存在，这不能通过标准的实验室调查诊断。
Background Peroxisomes are organelles that proliferate continuously and play an indispensable role in human metabolism. Consequently, peroxisomal gene defects can cause multiple, often severe disorders, including the peroxisome biogenesis disorders. Currently, 13 different PEX proteins have been implicated in various stages of peroxisome assembly and protein import. Defects in any of these proteins result in a peroxisome biogenesis disorder. The authors present here a novel genetic defect specifically affecting the division of peroxisomes.Methods The authors have studied biochemical and microscopical peroxisomal parameters in cultured patient fibroblasts, sequenced candidate PEX genes and determined the consequence of the identified PEX11 beta gene defect on peroxisome biogenesis in patient fibroblasts at different temperatures.Results The patient presented with congenital cataracts, mild intellectual disability, progressive hearing loss, sensory nerve involvement, gastrointestinal problems and recurrent migraine-like episodes. Although microscopical investigations of patient fibroblasts indicated a clear defect in peroxisome division, all biochemical parameters commonly used for diagnosing peroxisomal disorders were normal. After excluding mutations in all PEX genes previously implicated in peroxisome biogenesis disorders, it was found that the defect was caused by a homozygous non-sense mutation in the PEX11 beta gene. The peroxisome division defect was exacerbated when the patient's fibroblasts were cultured at 40 degrees C, which correlated with a marked decrease in the expression of PEX11 gamma.Conclusions This novel isolated defect in peroxisome division expands the clinical and genetic spectrum of peroxisomal disorders and indicates that peroxisomal defects exist, which cannot be diagnosed by standard laboratory investigations.