TARDBP p.G376D mutation, found in rapid progressive familial ALS, induces mislocalization of TDP-43

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease which causes the progressive weakness and atrophy of limbs and respiratory muscles, resulting in death within 3-5 years of onset.Targeted next-generation sequencing has enabled a comprehensive analysis of ALS disease-causing genes [1].However, a method to confirm the pathogenicity of variants of unknown significance (VUS) remains to be elucidated.The previously reported variants require validation if they are not isolated in the designated family members.For example, we have reported the first Asian familial ALS case with TARDBP p.G376D mutation [1], which was previously reported as a familial ALS-linked mutation in European familial cases [2,3].In the present study, we focused on TARDBP and the detailed clinical profile of the patient.We also examined TARDBP p.G376D pathogenicity using overexpression cell models.