A Missense Mutation in SLC33A1, which Encodes the Acetyl-CoA Transporter, Causes Autosomal-Dominant Spastic Paraplegia (SPG42)
A Missense Mutation in SLC33A1, which Encodes the Acetyl-CoA Transporter, Causes Autosomal-Dominant Spastic Paraplegia (SPG42)
复制标题
编码乙酰辅酶A转运蛋白的 SLC33A1 中的错义突变导致常染色体显性痉挛性截瘫 (SPG42)
DOI：
10.1016/j.ajhg.2008.11.003
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发表时间：
2008-12-12
影响因子：
9.8
通讯作者：
Gong, Yaoqin
中科院分区：
文献类型：
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作者：
Lin, Pengfei;Li, Jianwei;Gong, Yaoqin
遗传性痉挛性截瘫 (HSP) 的特征是腿部进行性双侧痉挛，通常是由皮质脊髓束中运动轴突发育障碍或退化引起的。家庭间和家庭内的发病年龄和痉挛严重程度存在相当大的差异。遗传学研究还表明，多条染色体上有数十个基因位点与 HSP 相关。通过对常染色体显性遗传的HSP家系的连锁研究，我们将致病基因定位到3q24-q26。对候选基因的筛选表明，HSP 是由乙酰辅酶 A 转运蛋白基因 (SLC33A1) 的错义突变引起的。据预测，错义突变会导致密码子 113 (p.S113R) 处高度保守的丝氨酸变为精氨酸，从而破坏转运蛋白中的第二个跨膜结构域，并反转所有下降结构域的方向。敲除斑马鱼中的 Slc33a1 会导致尾巴呈曲线形，并且脊髓轴突生长有缺陷。尽管野生型人类SLC33A1能够挽救斑马鱼中因Slc33a1敲低而引起的表型，但突变体SLC33A1（p.S113R）却不能，这表明S113R突变使SLC33A1失去功能，并且野生型等位基因不足以维持人类长运动轴突的生长和维持 杂合子。因此，我们的研究说明了乙酰辅酶A转运蛋白在运动神经元发育和功能中的关键作用。
Hereditary spastic paraplegias (HSPs), characterized by progressive and bilateral spasticity of the legs, are usually caused by developmental failure or degeneration of motor axons in the corticospinal tract. There are considerable interfamilial and intrafamilial variations in age at onset and severity of spasticity. Genetic studies also showed that there are dozens of genetic loci, on multiple chromosomes, that are responsible for HSPs. Through linkage study of a pedigree of HSP with autosomal-dominant inheritance, we mapped the causative gene to 3q24-q26. Screening of candidate genes revealed that the HSP is caused by a missense mutation in the gene for acetyl-CoA transporter (SLC33A1). It is predicted that the missense mutation, causing the change of the highly conserved serine to arginine at the codon 113 (p. S113R), disrupts the second transmembrane domain in the transporter and reverses the orientation of all of the descending domains. Knockdown of Slc33a1 in zebrafish caused a curve-shaped tail and defective axon outgrowth from the spinal cord. Although the wild-type human SLC33A1 was able to rescue the phenotype caused by Slc33a1 knockdown in zebrafish, the mutant SLC33A1 (p.S113R) was not, suggesting that S113R mutation renders SLC33A1 nonfunctional and one that wild-type allele is not sufficient for sustaining the outgrowth and maintenance of long motor axons in human heterozygotes. Thus, our study illustrated a critical role of acetyl-CoA transporter in motor-neuron development and function.