Homozygous mutation in MFSD2A, encoding a lysolipid transporter for docosahexanoic acid, is associated with microcephaly and hypomyelination
Homozygous mutation in MFSD2A, encoding a lysolipid transporter for docosahexanoic acid, is associated with microcephaly and hypomyelination
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DOI：
10.1007/s10048-018-0556-6
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发表时间：
2018-12-01
期刊：
影响因子：
2.2
通讯作者：
Edvardson, Shimon
中科院分区：
文献类型：
--
作者：
Harel, Tamar;Quek, Debra Q. Y.;Edvardson, Shimon
主要易化剂超家族含结构域蛋白2A（MFSD 2A）是血脑屏障的组成部分，其功能是将溶血磷脂酰胆碱（LPC）转运到中枢神经系统中。LPC，如源自二十二碳六烯酸（DHA）的LPC，对于神经发生和神经元的维持是不可或缺的，但不能在脑内合成，并且依赖于MFSD 2A用于脑摄取。最近的研究表明，致死性和非致死性小头畸形综合征中存在MFSD 2A突变，其严重程度与转运蛋白的残留活性相关。我们描述了两个有共同父母祖先的兄弟姐妹，在他们中我们发现了MFSD 2A的纯合错义突变（c.1205C>A; p.Pro402His）。这两个受影响的个人有小头畸形，肌张力减退，appericular痉挛，肌张力障碍，斜视，和全球发展迟缓。神经影像学显示白色物质缺乏，侧脑室扩大。血浆溶血磷脂酰胆碱（LPC）水平升高，反映脑转运减少。对p.Pro402His突变蛋白的基于细胞的研究表明，尽管具有非致死性的减毒表型，但转运蛋白的活性完全丧失。MFSD 2A相关基因型和表型的汇总数据表明，其他因素，如营养补充或修改遗传因素，可能会调节疾病的严重程度，并要求考虑受影响个体的治疗方案。
The major facilitator superfamily domain-containing protein 2A (MFSD2A) is a constituent of the blood-brain barrier and functions to transport lysophosphatidylcholines (LPCs) into the central nervous system. LPCs such as that derived from docosahexanoic acid (DHA) are indispensable to neurogenesis and maintenance of neurons, yet cannot be synthesized within the brain and are dependent on MFSD2A for brain uptake. Recent studies have implicated MFSD2A mutations in lethal and non-lethal microcephaly syndromes, with the severity correlating to the residual activity of the transporter. We describe two siblings with shared parental ancestry, in whom we identified a homozygous missense mutation (c.1205C>A; p.Pro402His) in MFSD2A. Both affected individuals had microcephaly, hypotonia, appendicular spasticity, dystonia, strabismus, and global developmental delay. Neuroimaging revealed paucity of white matter with enlarged lateral ventricles. Plasma lysophosphatidylcholine (LPC) levels were elevated, reflecting reduced brain transport. Cell-based studies of the p.Pro402His mutant protein indicated complete loss of activity of the transporter despite the non-lethal, attenuated phenotype. The aggregate data of MFSD2A-associated genotypes and phenotypes suggest that additional factors, such as nutritional supplementation or modifying genetic factors, may modulate the severity of disease and call for consideration of treatment options for affected individuals.