Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects.
复制标题
DOI：
10.1002/ana.25220
复制
发表时间：
2018-06
影响因子：
11.2
通讯作者：
Burmeister M
中科院分区：
文献类型：
--
作者：
Seong E;Insolera R;Dulovic M;Kamsteeg EJ;Trinh J;Brüggemann N;Sandford E;Li S;Ozel AB;Li JZ;Jewett T;Kievit AJA;Münchau A;Shakkottai V;Klein C;Collins CA;Lohmann K;van de Warrenburg BP;Burmeister M
明确隐性共济失调的新病因，包括脊髓小脑性共济失调伴跳动侵入性共济失调、痉挛性共济失调和痉挛截瘫。在一项国际合作中，我们独立地对7个患有隐性共济失调和/或痉挛截瘫的家系进行了外显子组测序。为了评估VPS13D突变的作用，我们评估了果蝇基因敲除模型，并研究了患者来源的成纤维细胞培养中的线粒体功能。外显子组测序发现在所有7个家系中都存在染色体1p36上VPS13D的复合杂合突变。这包括一个大的家庭，有5个受影响的兄弟姐妹，患有脊髓小脑性共济失调伴眼跳侵入(SCASI)，或脊髓小脑性共济失调，隐性，4型，SCAR4型。在该家系中发现与染色体1p36连锁，LOD评分为3.1。我们的12名患者的表型谱是广泛的。虽然大多数患者表现为共济失调，但有5名患者存在额外或主要的痉挛。发病年龄从婴儿期到39岁不等，症状进展缓慢，包括5名患者失去独立行走能力。除两名患者外，所有患者中一名患者携带功能丧失(无义或剪接点)突变，另一名患者携带错义突变。敲除或移除果蝇神经元中的Vps13D会导致线粒体形态的改变和沿轴突的线粒体分布受损。患者成纤维细胞的形态和功能发生了变化，包括能量产生减少。我们的研究表明，VPS13D的复合杂合突变会导致沿共济失调-痉挛频谱的运动障碍，使VPS13D成为第四个与神经疾病有关的VPS13类似基因。
To identify novel causes of recessive ataxias, including spinocerebellar ataxia with saccadic intrusions, spastic ataxias and spastic paraplegia. In an international collaboration, we independently performed exome sequencing in seven families with recessive ataxia and/or spastic paraplegia. To evaluate the role of VPS13D mutations, we evaluated a Drosophila knock-out model and investigated mitochondrial function in patient-derived fibroblast cultures. Exome sequencing identified compound heterozygous mutations in VPS13D on chromosome 1p36 in all seven families. This included a large family with 5 affected siblings with spinocerebellar ataxia with saccadic intrusions (SCASI), or spinocerebellar ataxia, recessive, type 4, SCAR4. Linkage to chromosome 1p36 was found in this family with a LOD score of 3.1. The phenotypic spectrum in our 12 patients was broad. Although most presented with ataxia, additional or predominant spasticity was present in 5 patients. Disease onset ranged from infancy to 39 years, and symptoms were slowly progressive and included loss of independent ambulation in 5. All but two patients carried a loss-of-function (nonsense or splice site) mutation on one and a missense mutation on the other allele. Knock-down or removal of Vps13D in Drosophila neurons led to changes in mitochondrial morphology and impairment in mitochondrial distribution along axons. Patient fibroblasts showed altered morphology and functionality including reduced energy production. Our study demonstrates that compound heterozygous mutations in VPS13D cause movement disorders along the ataxia-spasticity spectrum, making VPS13D the fourth VPS13 paralog involved in neurological disorders.
登录
查看更多内容
影响因子：
14.9
作者：
Desmet FO;Hamroun D;Lalande M;Collod-Béroud G;Claustres M;Béroud C
通讯作者：
Béroud C
影响因子：
9.8
作者：
Kolehmainen, J;Wilkinson, R;Manson, FDC
通讯作者：
Manson, FDC
影响因子：
9.8
作者：
Hennies, HC;Rauch, A;Horn, D
通讯作者：
Horn, D
影响因子：
3.9
作者：
Balikova, I.;Lehesjoki, A-E.;Vermeesch, J. R.
通讯作者：
Vermeesch, J. R.
影响因子：
--
作者：
Beaudin M;Klein CJ;Rouleau GA;Dupré N
通讯作者：
Dupré N