Screening of SOD1, FUS and TARDBP genes in patients with amyotrophic lateral sclerosis in central-southern China

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease affecting motor neurons of the brain, brainstem and spinal cord. To date, mutations in more than 30 genes have been linked to the pathogenesis of ALS. Among them, SOD1, FUS and TARDBP are ranked as the three most common genes associated with ALS. However, no mutation analysis has been reported in central-southern China. In this study, we sequenced SOD1, FUS and TARDBP in a central-southern Chinese cohort of 173 patients with ALS (15 familial ALS and 158 sporadic ALS) to detect mutations. As a result, five missense mutations in SOD1, namely, p.D101N, p.D101G, p.C111Y, p.N86S and p.V87A, were identified in three unrelated familial probands and three sporadic cases; two mutations in FUS were found in two unrelated familial probands, including an insertion mutation (p.P525_Y526insY) and a missense mutation (p.R521H); no variants of TARDBP were observed in patients. Therefore, SOD1 mutations were present in 20.0% of familial ALS patients and 1.9% of sporadic ALS patients, while FUS mutations were responsible for 13.3% of familial ALS cases, and TARDBP mutations were rare in either familial or sporadic ALS cases. This study broadens the known mutational spectrum in patients with ALS and further demonstrates the necessity for genetic screening in ALS patients from central-southern China.

High frequency of the TARDBP p.M337 V mutation among south-eastern Chinese patients with familial amyotrophic lateral sclerosis

“…In this study, among the 7 unrelated SOD1 - and FUS -negative ALS families, we detected 2 TARDBP mutations (c.1009A > G, p.M337 V and c.1042G > T, p.G348C) in 5 families. Importantly, 4 families carried the same TARDBP mutation, c.1009A > G, p.M337 V. Hou L et al screened SOD1 , TARDBP , and FUS gene mutations in ALS patients from central-southern China and revealed that SOD1 (20%) and FUS (13.3%) mutations were the main causal mutations in familial ALS, but they did not detect any TARDBP -linked ALS families [ 9 ]. In a Brazilian research centre, Chadi G et al reported that the most common gene mutations in familial ALS were VAPB (43.6%), C9orf72 (12.8%), and SOD1 (7.7%), whereas no FUS or TARDBP mutations were detected in any familial ALS subjects [ 10 ].…”

Biomarkers in Motor Neuron Disease: A State of the Art Review

“…Other inflammatory markers have shown varying results, such as C reactive protein (CRP), which showed no differences in plasma (132) or whole blood (60) at baseline. In serum, CRP was increased in ALS and did not associate with ALS risk or survival in one study (133), but correlated with ALSFRS-R and survival in another (134).…”

“…A recent analysis of trial data from over 1,200 people with ALS found strong longitudinal correlations between serum creatinine and ALSFRS-R score, muscle strength, and overall mortality, indicating that using serum creatinine in trials over 18 months in length would allow a reduction in sample size by 21.5% (141). Lending further support to this pathway as a useful biomarker of muscle denervation, serum creatine kinase (CK) is increased in plasma (132), and serum (140, 142) and correlates with survival in some studies (140, 142). This discrepancy may be attributed to differing rates of disease progression.…”

“…An increase in ferritin, suggesting iron misregulation which promotes oxidative stress, is present in plasma (132) and serum of ALS patients (85, 136, 162), with higher levels associated with poorer survival in some studies (123, 136, 162), but not all (85).…”

Identification of CHCHD2 mutations in patients with Alzheimer's disease, amyotrophic lateral sclerosis and frontotemporal dementia in China

“…Neuroradiological examinations for example MRI, was assessed with patients diagnosed as probable or possible AD and FTD in this study. We have excluded AD, FTD and ALS patients carrying disease-causing gene like PSEN1, PSEN2, APP, MAPT, GRN, C9orf72, TREM2, CHCHD10, SOD1, TARDBP, FUS (3,(16)(17)(18)(19)(20). Additionally, the APOE genotype was available for all AD patients.…”