The p150 subunit of dynactin gene in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a multifactorial disease in which mostly unidentified genetic factors in conjunction with environmental agents affect its clinical expression. Neurodegeneration has emerged as a significant contributor to CNS lesions in MS. Genetic susceptibility of the neuron may determine the degree of ensuing neurodegeneration after an inflammatory attack. We have recently described mutations in the p150 subunit of the molecular motor dynactin (DCTN1) in amyotrophic lateral slerosis (ALS) and frontotemporal dementia (FTD) that may predispose different neuron types to degeneration. Given the common features of neurodegeneration in MS, ALS and FTD, we raised the question whether genetic variants in the DCTN1 gene may constitute a risk factor for MS. We conducted a DCTN1 mutation analysis in 192 patients with MS (96 patients with relapsing-remitting MS and 96 with primary progressive MS) and the same number of unrelated controls. In MS, no mutations in the DCTN1 gene have been found. Three novel heterozygous sequence variants (R532L, T1249I, I196V) of the DTCN1 gene were detected in four controls. However, no significant genetic association of the three sequence alterations with the absence of MS has been found. We conclude that DCTN1 may not contribute to the genetic background of neurodegeneration in MS. Our findings support the notion that the DCTN1 gene is highly heterogeneous. DCTN1 sequence variants are also found under normal conditions and their pathogenetic relevance is far from being completely understood.