Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
Mutation in CPT1C Associated With Pure Autosomal Dominant Spastic Paraplegia.
复制标题
DOI：
10.1001/jamaneurol.2014.4769
复制
发表时间：
2015-05
期刊：
影响因子：
29
通讯作者：
Fischbeck KH
中科院分区：
文献类型：
--
作者：
Rinaldi C;Schmidt T;Situ AJ;Johnson JO;Lee PR;Chen KL;Bott LC;Fadó R;Harmison GH;Parodi S;Grunseich C;Renvoisé B;Biesecker LG;De Michele G;Santorelli FM;Filla A;Stevanin G;Dürr A;Brice A;Casals N;Traynor BJ;Blackstone C;Ulmer TS;Fischbeck KH
与遗传性痉挛性截瘫（HSP）有关的基因家族正在迅速扩大，这主要是由于下一代DNA测序方法的广泛应用。然而，许多患者仍然无法获得基因诊断。确定一种新形式的纯常染色体显性热休克蛋白的遗传原因。我们检查并随访了一个到三级转诊中心评估HSP的家庭，直到2014年8月。对同一家系的4例患者进行全外显子测序，并结合连锁分析。桑格测序用于确认候选变异体在该家族的其余受影响和未受影响的成员中的存在，并筛选具有HSP的额外患者。研究对象为来自一个3代遗传来源不明的纯成人型常染色体显性HSP家族的5名受影响者和6名未受影响者。此外，筛选了163名遗传原因不明的纯HSP无关参与者。肉毒碱棕榈酰转移酶（CPT 1C）基因的神经元亚型突变。我们确定了CPT 1C外显子3中的核苷酸替换c.109C>T，这决定了基因产物中进化上保守的Cys残基对Arg的碱基替换。这种变异与疾病表型严格共分离，并且在在线单核苷酸多态性数据库和对照参与者的712个额外外显子中不存在。我们发现，CPT 1C，其定位于内质网，在运动神经元中表达，并与atlastin-1相互作用，atlastin-1是一种由ATL 1基因编码的内质网蛋白，已知在纯HSP中突变。核磁共振光谱研究表明，突变改变了蛋白质构象，并减少了细胞中过表达的脂滴的平均（SD）数量（213.0 [46.99] vs 81.9 [14.2]; P <0.01）和大小（0.29 [0.01] vs 0.26 [0.01]; P <0.05）。我们还观察到，与野生型小鼠相比，从Cpt 1c −/−小鼠分离的原代皮层神经元中平均（SD）脂滴减少（1.0 [0.12] vs 0.44 [0.05]; P < .001），表明突变的显性负性机制。这项研究扩展了常染色体显性HSP的遗传学，并且是第一个，据我们所知，将CPT 1C突变与人类疾病联系起来。CPT 1C突变与脂滴生物发生变化的关联支持了HSP发病机制中脂质介导的信号转导改变的作用。
The family of genes implicated in hereditary spastic paraplegias (HSPs) is quickly expanding, mostly owing to the widespread availability of next-generation DNA sequencing methods. Nevertheless, a genetic diagnosis remains unavailable for many patients. To identify the genetic cause for a novel form of pure autosomal dominant HSP. We examined and followed up with a family presenting to a tertiary referral center for evaluation of HSP for a decade until August 2014. Whole-exome sequencing was performed in 4 patients from the same family and was integrated with linkage analysis. Sanger sequencing was used to confirm the presence of the candidate variant in the remaining affected and unaffected members of the family and screen the additional patients with HSP. Five affected and 6 unaffected participants from a 3-generation family with pure adult-onset autosomal dominant HSP of unknown genetic origin were included. Additionally, 163 unrelated participants with pure HSP of unknown genetic cause were screened. Mutation in the neuronal isoform of carnitine palmitoyl-transferase (CPT1C) gene. We identified the nucleotide substitution c.109C>T in exon 3 of CPT1C, which determined the base substitution of an evolutionarily conserved Cys residue for an Arg in the gene product. This variant strictly cosegregated with the disease phenotype and was absent in online single-nucleotide polymorphism databases and in 712 additional exomes of control participants. We showed that CPT1C, which localizes to the endoplasmic reticulum, is expressed in motor neurons and interacts with atlastin-1, an endoplasmic reticulum protein encoded by the ATL1 gene known to be mutated in pure HSPs. The mutation, as indicated by nuclear magnetic resonance spectroscopy studies, alters the protein conformation and reduces the mean (SD) number (213.0 [46.99] vs 81.9 [14.2]; P < .01) and size (0.29 [0.01] vs 0.26 [0.01]; P < .05) of lipid droplets on overexpression in cells. We also observed a reduction of mean (SD) lipid droplets in primary cortical neurons isolated from Cpt1c−/− mice as compared with wild-type mice (1.0 [0.12] vs 0.44 [0.05]; P < .001), suggesting a dominant negative mechanism for the mutation. This study expands the genetics of autosomal dominant HSP and is the first, to our knowledge, to link mutation in CPT1C with a human disease. The association of the CPT1C mutation with changes in lipid droplet biogenesis supports a role for altered lipid-mediated signal transduction in HSP pathogenesis.
登录
查看更多内容
影响因子：
13.9
作者：
Blackstone C
通讯作者：
Blackstone C
影响因子：
7
作者：
Biesecker, Leslie G.;Mullikin, James C.;Green, Eric D.
通讯作者：
Green, Eric D.
DOI：
10.1073/pnas.1103267108
发表时间：
2011-06-07
影响因子：
11.1
作者：
Gao, Su;Zhu, Guangjing;Lopaschuk, Gary D.
通讯作者：
Lopaschuk, Gary D.
Cpt1c 敲除小鼠对高脂饮食引起的葡萄糖不耐受的敏感性增强，涉及肝糖异生作用增强和骨骼肌葡萄糖摄取减少
影响因子：
8.2
作者：
Gao, X. F.;Chen, W.;Wu, D.
通讯作者：
Wu, D.
影响因子：
4.8
作者：
Lopez-Vinas, Eduardo;Bentebibel, Assia;Gomez-Puertas, Paulino
通讯作者：
Gomez-Puertas, Paulino