SLC1A4 mutations cause a novel disorder of intellectual disability, progressive microcephaly, spasticity and thin corpus callosum
SLC1A4 mutations cause a novel disorder of intellectual disability, progressive microcephaly, spasticity and thin corpus callosum
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DOI：
10.1111/cge.12637
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发表时间：
2015-10-01
影响因子：
3.5
通讯作者：
Ben Zeev, B.
中科院分区：
文献类型：
--
作者：
Heimer, G.;Marek-Yagel, D.;Ben Zeev, B.
两名不相关的患者均表现出明显的整体发育迟缓、严重进行性小头畸形、癫痫发作、痉挛和胼胝体薄弱（CC），接受了三重全外显子组测序。在与表型相关的任何已知基因中均未发现候选变异。然而，交叉患者的数据表明，他们都表现出 SLC1A4 基因的致病性变异，该基因编码丝氨酸和其他中性氨基酸的 ASCT1 转运蛋白。阿什肯纳兹患者是有害错义 c.766G>A, p.(E256K) 突变的纯合子，而阿什肯纳兹-伊拉克患者是该突变和无义 c.945delTT, p.(Leu315Hisfs*42) 突变的复合杂合子。结构预测表明无义突变截断了蛋白质的重要部分，并推测错义突变导致功能破坏。这两种突变在一般人群数据库中都极为罕见，然而，在 1:100 犹太德系犹太人对照中以杂合模式发现了错义突变，表明德系犹太人中的携带率较高。我们得出结论，SLC1A4 是一种新型神经系统疾病的致病基因，该疾病表现为明显的智力障碍、严重的产后小头畸形、痉挛和薄 CC。 SLC1A4 在从星形胶质细胞到神经元的丝氨酸转运中的作用表明了这种疾病可能的病理机制，并暗示了一种潜在的治疗方法。
Two unrelated patients, presenting with significant global developmental delay, severe progressive microcephaly, seizures, spasticity and thin corpus callosum (CC) underwent trio whole-exome sequencing. No candidate variant was found in any known genes related to the phenotype. However, crossing the data of the patients illustrated that they both manifested pathogenic variants in the SLC1A4 gene which codes the ASCT1 transporter of serine and other neutral amino acids. The Ashkenazi patient is homozygous for a deleterious missense c.766G>A, p.(E256K) mutation whereas the Ashkenazi-Iraqi patient is compound heterozygous for this mutation and a nonsense c.945delTT, p.(Leu315Hisfs*42) mutation. Structural prediction demonstrates truncation of significant portion of the protein by the nonsense mutation and speculates functional disruption by the missense mutation. Both mutations are extremely rare in general population databases, however, the missense mutation was found in heterozygous mode in 1:100 Jewish Ashkenazi controls suggesting a higher carrier rate among Ashkenazi Jews. We conclude that SLC1A4 is the disease causing gene of a novel neurologic disorder manifesting with significant intellectual disability, severe postnatal microcephaly, spasticity and thin CC. The role of SLC1A4 in the serine transport from astrocytes to neurons suggests a possible pathomechanism for this disease and implies a potential therapeutic approach.