Laboratory Genetic Metabolic Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
J Med Genet. 2012 May;49(5):307-13. doi: 10.1136/jmedgenet-2012-100778.
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.
The authors have studied biochemical and microscopical peroxisomal parameters in cultured patient fibroblasts, sequenced candidate PEX genes and determined the consequence of the identified PEX11β gene defect on peroxisome biogenesis in patient fibroblasts at different temperatures.
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 PEX11β gene. The peroxisome division defect was exacerbated when the patient's fibroblasts were cultured at 40°C, which correlated with a marked decrease in the expression of PEX11γ.
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.
过氧化物酶体是不断增殖的细胞器，在人类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、常为严重的疾病，包括过氧化物酶体生物发生障碍。目前，已有 13 种不同的 PEX 蛋白参与过氧化物酶体组装和蛋白输入的各个阶段。这些蛋白中的任何一种缺陷都会导致过氧化物酶体生物发生障碍。作者在此介绍一种专门影响过氧化物酶体分裂的新的遗传缺陷。
作者研究了培养的患者成纤维细胞中的生化和显微镜下过氧化物酶体参数，对候选 PEX 基因进行测序，并确定了鉴定的 PEX11β 基因突变对不同温度下患者成纤维细胞过氧化物酶体生物发生的影响。
患者表现为先天性白内障、轻度智力障碍、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。尽管患者成纤维细胞的显微镜检查表明过氧化物酶体分裂明显缺陷，但所有用于诊断过氧化物酶体疾病的生化参数均正常。在排除所有先前与过氧化物酶体生物发生障碍相关的 PEX 基因的突变后，发现该缺陷是由 PEX11β 基因的纯合无义突变引起的。当患者的成纤维细胞在 40°C 培养时，过氧化物酶体分裂缺陷加剧，这与 PEX11γ 的表达明显减少相关。
这种新型孤立的过氧化物酶体分裂缺陷扩展了过氧化物酶体疾病的临床和遗传谱，并表明存在无法通过标准实验室检查诊断的过氧化物酶体缺陷。
