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首页> 外文期刊>Biochimica et biophysica acta. Molecular basis of disease: BBA >CYP4F2 affects phenotypic outcome in adrenoleukodystrophy by modulating the clearance of very long-chain fatty acids
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CYP4F2 affects phenotypic outcome in adrenoleukodystrophy by modulating the clearance of very long-chain fatty acids

机译：CYP4F2通过调节非常长链脂肪酸的清除影响肾上腺白质营养不良的表型预后

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摘要

X-linked adrenoleukodystrophy (ALD) is a severe neurodegenerative disorder caused by the accumulation of very long-chain fatty acids (VLCFA) due to mutations in the ABCD1 gene. The phenotypic spectrum ranges from a fatal cerebral demyelinating disease in childhood (cerebral ALD) to a progressive myelopathy without cerebral involvement in adulthood (adrenomyeloneuropathy). Because ABCD1 mutations have no predictive value with respect to clinical outcome a role for modifier genes was postulated. We report that the CYP4F2 polymorphism rs2108622 increases the risk of developing cerebral ALD in Caucasian patients. The rs2108622 polymorphism (c.1297G > A) results in an amino acid substitution valine for methionine at position 433 (p.V433M). Using cellular models of VLCFA accumulation, we show that p.V433M decreases the conversion of VLCFA into very long-chain dicarboxylic acids by co-oxidation, a potential escape route for the deficient peroxisomal (3-oxidation of VLCFA in ALD. Although p.V433M does not affect the catalytic activity of CYP4F2 it reduces CYP4F2 protein levels markedly. These findings open perspectives for therapeutic interventions in a disease with currently limited treatment options. (C) 2016 Elsevier B.V. All rights reserved.
机译：X联肾上腺皮质营养不良（ALD）是一种严重的神经退行性疾病，由ABCD1基因突变导致超长链脂肪酸（VLCFA）积累引起。表型范围从儿童时期的致命性脑脱髓鞘疾病（脑ALD）到没有大脑参与成年期的进行性脊髓病（肾上腺髓质神经病）。因为ABCD1突变对于临床结果没有预测价值，所以推测修饰基因的作用。我们报告CYP4F2多态性rs2108622增加了白种人患者发展为脑ALD的风险。 rs2108622多态性（c.1297G> A）导致在位置433（p.V433M）处甲硫氨酸的氨基酸取代缬氨酸。使用VLCFA积累的细胞模型，我们显示p.V433M通过共氧化减少了VLCFA向长链二羧酸的转化，共氧化是过氧化物酶体缺陷（ALD中VLCFA的3-氧化）的潜在逃逸途径。 V433M不会影响CYP4F2的催化活性，它会显着降低CYP4F2的蛋白水平，这些发现为目前治疗选择有限的疾病的治疗性干预开辟了前景（C）2016 Elsevier BV保留所有权利。

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