Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany.
Mov Disord. 2022 Feb;37(2):375-383. doi: 10.1002/mds.28821. Epub 2021 Oct 11.
In a large pedigree with an unusual phenotype of spastic paraplegia or dystonia and autosomal dominant inheritance, linkage analysis previously mapped the disease to chromosome 2q24-2q31.
The aim of this study is to identify the genetic cause and molecular basis of an unusual autosomal dominant spastic paraplegia and dystonia.
Whole exome sequencing following linkage analysis was used to identify the genetic cause in a large family. Cosegregation analysis was also performed. An additional 384 individuals with spastic paraplegia or dystonia were screened for pathogenic sequence variants in the adenosine triphosphate (ATP) synthase membrane subunit C locus 3 gene (ATP5MC3). The identified variant was submitted to the "GeneMatcher" program for recruitment of additional subjects. Mitochondrial functions were analyzed in patient-derived fibroblast cell lines. Transgenic Drosophila carrying mutants were studied for movement behavior and mitochondrial function.
Exome analysis revealed a variant (c.318C > G; p.Asn106Lys) (NM_001689.4) in ATP5MC3 in a large family with autosomal dominant spastic paraplegia and dystonia that cosegregated with affected individuals. No variants were identified in an additional 384 individuals with spastic paraplegia or dystonia. GeneMatcher identified an individual with the same genetic change, acquired de novo, who manifested upper-limb dystonia. Patient fibroblast studies showed impaired complex V activity, ATP generation, and oxygen consumption. Drosophila carrying orthologous mutations also exhibited impaired mitochondrial function and displayed reduced mobility.
A unique form of familial spastic paraplegia and dystonia is associated with a heterozygous ATP5MC3 variant that also reduces mitochondrial complex V activity.
在一个具有痉挛性截瘫或肌张力障碍等不常见表型和常染色体显性遗传的大型家系中，先前的连锁分析将该疾病定位在 2q24-2q31 染色体上。
本研究旨在确定一种不常见的常染色体显性痉挛性截瘫和肌张力障碍的遗传原因和分子基础。
采用连锁分析后的全外显子组测序，鉴定一个大家庭的遗传原因。还进行了共分离分析。在 384 名患有痉挛性截瘫或肌张力障碍的个体中筛选腺苷三磷酸（ATP）合酶膜亚基 C 位点 3 基因（ATP5MC3）中的致病序列变异。鉴定出的变异体被提交给“GeneMatcher”程序，以招募更多的研究对象。分析患者来源的成纤维细胞系中的线粒体功能。携带突变的转基因果蝇用于研究运动行为和线粒体功能。
外显子组分析显示，一个常染色体显性痉挛性截瘫和肌张力障碍的大型家系中存在 ATP5MC3 变异（c.318C>G；p.Asn106Lys）（NM_001689.4），该变异与受累个体共分离。在另外 384 名患有痉挛性截瘫或肌张力障碍的个体中未发现变异。GeneMatcher 确定了一名具有相同遗传变化的个体，该个体为新发，表现为上肢肌张力障碍。患者成纤维细胞研究显示复合物 V 活性、ATP 生成和耗氧量受损。携带同源突变的果蝇也表现出线粒体功能受损，并表现出运动能力下降。
一种独特的家族性痉挛性截瘫和肌张力障碍与杂合性 ATP5MC3 变异有关，该变异还降低了线粒体复合物 V 的活性。
