Recessive Mutations in ELOVL4 Cause Ichthyosis, Intellectual Disability, and Spastic Quadriplegia
Recessive Mutations in ELOVL4 Cause Ichthyosis, Intellectual Disability, and Spastic Quadriplegia
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DOI：
10.1016/j.ajhg.2011.10.011
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发表时间：
2011-12-09
影响因子：
9.8
通讯作者：
Alkuraya, Fowzan S.
中科院分区：
文献类型：
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作者：
Aldahmesh, Mohammed A.;Mohamed, Jawahir Y.;Alkuraya, Fowzan S.
超长链脂肪酸（VLCFAs）在膜结构和细胞信号传导中起着重要作用，其对人类健康的贡献日益受到重视。脂肪酸延伸酶催化VLCFA合成中的第一步和限速步骤。已知编码其中一种延长酶的基因HPLVL 4的杂合突变会导致人类黄斑变性和小鼠视网膜异常。然而，在人类中尚未观察到双等位基因VL 4突变，并且具有纯合突变的小鼠模型在出生后数小时内由于表皮水屏障缺陷而死亡。在这里，我们报告了两个人的隐性ESTVL 4突变的autoESTRome分析和外显子组测序相结合揭示。这些人表现出鱼鳞病，癫痫发作，精神发育迟滞和痉挛的临床特征，类似Sjogren-Larsson综合征（SLS）的星座，但提出了更严重的神经系统表型。我们的研究结果确定隐性突变的VL 4作为神经鱼鳞病的原因，并强调VLCFA合成在大脑和皮肤发育的重要性。
Very-long-chain fatty acids (VLCFAs) play important roles in membrane structure and cellular signaling, and their contribution to human health is increasingly recognized. Fatty acid elongases catalyze the first and rate-limiting step in VLCFA synthesis. Heterozygous mutations in ELOVL4, the gene encoding one of the elongases, are known to cause macular degeneration in humans and retinal abnormalities in mice. However, biallelic ELOVL4 mutations have not been observed in humans, and murine models with homozygous mutations die within hours of birth as a result of a defective epidermal water barrier. Here, we report on two human individuals with recessive ELOVL4 mutations revealed by a combination of autozygome analysis and exome sequencing. These individuals exhibit clinical features of ichthyosis, seizures, mental retardation, and spasticity-a constellation that resembles Sjogren-Larsson syndrome (SLS) but presents a more severe neurologic phenotype. Our findings identify recessive mutations in ELOVL4 as the cause of a neuro-ichthyotic disease and emphasize the importance of VLCFA synthesis in brain and cutaneous development.