Association between novel TARDBP mutations and Chinese patients with amyotrophic lateral sclerosis

71 SALS patients and 5 FALS families with non-SOD1 mutations were screened for TARDBP mutations via direct sequencing.A novel heterozygous variation, Ser292Asn (875G>A), was identified in the proband and 4 asymptomatic relatives including the children of the dead patient from a FALS family. Thus the dead patient, the proband's brother, was speculated to carry Ser292Asn though his sample was unavailable to the detection. This variation was not found in 200 unrelated control subjects. A homology search of the TDP-43 protein in different species demonstrated that it was highly conserved. Also, it was predicted to be deleterious to protein function with SIFT-calculated probabilities of 0.00. Therefore, Ser292Asn is predicted to be a pathogenic mutation. In addition, we have found two silent mutations (Gly40Gly and Ala366Ala) and one novel polymorphism (239-18t>c).The present data have extended the spectrum of TARDBP mutations and polymorphisms, and supported the pathological role of TDP-43 in Chinese ALS patients.Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease and is characterized by progressive loss of upper and lower motor neurons from the spinal cord, brain stem and cerebral cortex, leading to paralysis and eventually death which is due to respiratory failure within 3-5 years after symptom onset [1]. Approximately 5-10% of ALS cases are familial (FALS) whereas the remaining patients are sporadic (SALS) [2]. About 15-20% of patients with autosomal dominant FALS have mutations in the copper-zinc superoxide dismutase 1 gene (SOD1), while mutations in other genes including alsin (ALS2), senataxin (SETX, ALS4), dynactin (DCTIN1), angiogenin (ANG), synaptobrevin-associated membrane protein B (VAPB, ALS8) and Fused in Sarcoma (FUS, ALS6) are described as rare causes of FALS [2-5]. Recently, a novel senataxin mutation has been reported in a SALS patient [6]. Ubiquitin-positive tau-negative neuronal cytoplasmic inclusion is the common patho