Vyshkina Tamara, Banisor Ileana, Shugart Yin Yao, Leist Thomas P, Kalman Bernadette
Department of Neurology, SLRHC, Columbia University, 432W 58th Street, New York, NY 10019, USA.
J Neurol Sci. 2005 Jan 15;228(1):55-64. doi: 10.1016/j.jns.2004.09.027.
A mitochondrial mechanism contributes to neurodegeneration in multiple sclerosis (MS). Genetic variants of Complex I genes may influence the nature of tissue response to inflammation in the central nervous system (CNS).
Complex I is encoded by seven mitochondrial and 38 nuclear genes. Many of the nuclear genes colocalize with regions where full genome scans detected linkage in MS. Previous studies revealed an association between variants of mitochondrial (mt)DNA encoded subunits of Complex I and MS. Biochemical studies suggested a functional involvement of Complex I in the degenerative processes downstream to inflammatory injury in the CNS.
Patients with all MS phenotypes were included. DNA specimens of affected sib pair, trio and multiplex families were studied. Single nucleotide polymorphisms (SNP) were determined by using the Taqman assay. The association of MS with nuclear DNA encoded alleles and haplotypes of Complex I was tested by the pedigree disequilibrium test (PDT) and by the transmit program in the families. Haplotypes were further investigated by using ldmax (GOLD). The association of mtDNA encoded variants with MS was tested by the Fisher's Exact Test.
The previously identified MS-associated mtDNA variants and haplotypes were not increased in mothers as compared to fathers in these families. However, an association of all clinical phenotypes with haplotypes within NDUFS5 (1p34.2-p33), NDUFS7 (19p13) and NDUFA7 (19p13) was detected. The inclusion of families with primary progressive (PP)-MS phenotype did not modify the outcome and, as a subgroup alone, did not have a sufficient size to draw conclusion regarding phenotype specific associations.
SNP haplotypes within Complex I genes are associated with MS. Further studies are needed to refine the identification of disease relevant variants nearby or within these haplotypes. Molecular and functional properties of Complex I subunits may offer novel explanations to better understand the relationship between inflammation and neurodegeneration.
线粒体机制促成了多发性硬化症（MS）中的神经退行性变。复合体I基因的遗传变异可能会影响中枢神经系统（CNS）对炎症的组织反应性质。
复合体I由7个线粒体基因和38个核基因编码。许多核基因与全基因组扫描在MS中检测到连锁的区域共定位。先前的研究揭示了复合体I的线粒体（mt）DNA编码亚基的变异与MS之间的关联。生化研究表明复合体I在CNS炎症损伤下游的退行性过程中发挥功能性作用。
纳入所有MS表型的患者。研究了患病同胞对、三联体和多重家庭的DNA样本。使用Taqman分析法确定单核苷酸多态性（SNP）。通过家系不平衡检验（PDT）以及家族中的传递程序来检测MS与复合体I的核DNA编码等位基因和单倍型之间的关联。使用ldmax（GOLD）进一步研究单倍型。通过Fisher精确检验来检测mtDNA编码变异与MS之间的关联。
在这些家庭中，与父亲相比，母亲中先前鉴定出的与MS相关的mtDNA变异和单倍型并未增加。然而，检测到所有临床表型与NDUFS5（1p34.2 - p33）、NDUFS7（19p13）和NDUFA7（19p13）内的单倍型存在关联。纳入原发性进展型（PP） - MS表型的家庭并未改变结果，并且作为一个单独的亚组，其规模不足以得出关于表型特异性关联的结论。
复合体I基因内的SNP单倍型与MS相关。需要进一步研究以更精确地鉴定这些单倍型附近或内部与疾病相关的变异。复合体I亚基的分子和功能特性可能为更好地理解炎症与神经退行性变之间的关系提供新的解释。
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