Phenotypic, Biological and Functional Consequences of Mutations in the SPG7 Gene at the Heterozygous State
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 11
- 试验地点
- 1
- 主要终点
- Mitochondrial respiratory activity measured by Seahorse analyser and quantification of mADN vs nuclear AND in activity in patients with neurological symptoms and one or two mutations in the SPG7 gene vs controls
研究概览
简要总结
Paraplegin, encoded by the SPG7 gene, is an ATP-dependent mAAA protease located in the inner mitochondrial membrane. Its function is not fully understood. Mutations in the SPG7 gene are responsible for spastic paraplegia type 7. Although spastic paraplegia type 7 is considered to be a recessive disease, some clinical observations also point to a detrimental effect of a variant in SPG7 in the heterozygous state. Thus, the presence of a single mutated variant of the SPG7 gene could be a risk factor for the development of neurological diseases. This has important implications for genetic counseling of patients and for the understanding of the function of the SPG7 protein and the mechanisms of disease development.
详细描述
Although spastic paraplegia type 7 is considered to be a recessive disease, some clinical observations also argue for a detrimental effect of a variant in SPG7 in the heterozygous state. Thus, the presence of a single mutated variant of the SPG7 gene could be a risk factor for the development of neurological diseases. This has important implications for genetic counseling of patients and for the understanding of the function of the SPG7 protein and the mechanisms of disease development. To date there have been no studies to specifically explore the pathogenic role of single heterozygous variants in the SPG7 gene.
The aim of this project is to fully characterize different models expressing single heterozygous SPG7 mutations in order to detect phenotypical, biological or functional alterations. In particular, the investigators will conduct analysis on fibroblasts from symptomatic patients with mutations in the SPG7 gene (homozygous, compound heterozygous or single heterozygous), and controls. Cellular models will be particularly useful in order to study an alteration in calcium homeostasis and in the response to ER stressors. In parallel, studies will be performed using the genetic animal model of Drosophila melanogaster.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 主要目的
- Basic Science
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •age > or equal to 18 years
- •presence of neurological symptoms compatible with GSP7 (ataxia, spasticity progressive external ophthalmoplegia, and/or optic atrophy)
- •presence of two mutations in the SPG7 gene (= recessive forms of SPG7) or of a single mutation in the simple heterozygous state in the absence of other genetic factors explaining the symptoms
- •Inclusion criteria for controls
- •Age > or equal to 18 years
- •Subject who is already undergoing neurosurgical intervention as part of the care pathway for an for an acquired, non-genetic neurological problem (e.g. herniated disc, narrow lumbar canal)
- •Non-inclusion Criteria of cases
- •Refusal to sign the written informed consent signed by the patient (or by his representative in case of a patient under guardianship.
- •Patients with specific contraindications for skin biopsy current anticoagulant treatment; any pathologies that may cause a risk of bleeding (e.g. hemophiliacs)
- •Refusal of the patient, of the guardian if necessary, to sign the informed consent to participate in the in the research
- •Not being a beneficiary of a social protection plan Patient deprived of liberty
- •Non-inclusion Criteria of controls
- •Patients with a genetic neurological disease or mitochondrial disease
- •Patients with specific contraindications for skin biopsy: current anticoagulant treatment; all pathologies that may cause a risk of bleeding (e.g. hemophilia)
- •Refusal to sign the informed consent to participate in the research
- •Not benefiting from a social protection plan
- •Patient deprived of liberty
- •Patient under guardianship or curatorship
排除标准
- 未提供
研究组 & 干预措施
Patients with neurological symptoms and two mutations in the SPG7 gene
Symptomatic patients with SPG7 mutations (homozygous or compound heterozygous)
干预措施: Skin biopsy (Other)
Patients with neurological symptoms and one mutation in the SPG7 gene
Patients presenting neurological symptoms corresponding to SPG7 disease (adult onset spastic ataxia with CPEO and/or optic atrophy) with only one mutation found in the SPG7 gene
干预措施: Skin biopsy (Other)
Controls
Patients without mutations in the SPG7 gene requiring spinal surgery because of a non-genetic neurologic disorders
干预措施: Skin biopsy (Other)
结局指标
主要结局
Mitochondrial respiratory activity measured by Seahorse analyser and quantification of mADN vs nuclear AND in activity in patients with neurological symptoms and one or two mutations in the SPG7 gene vs controls
时间窗: Inclusion
Mitochondrial dimension and morphology by electronic microscopy and quantification of mitochondrial motility by direct imaging activity in patients with neurological symptoms and one or two mutations in the SPG7 gene vs controls
时间窗: Inclusion
次要结局
- Mitochondrial calcium quantification after expression of a probe for calcium detection in patients with neurological symptoms and one or two mutations in the SPG7 gene vs controls(Inclusion)