Identification of TARDBP Gly298Ser as a founder mutation for amyotrophic lateral sclerosis in Southern China

Abstract

Background Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by predominant impairment of upper and lower motor neurons. Over 50 TARDBP mutations have been reported in both familial (FALS) and sporadic ALS (SALS). Some mutations in TARDBP, e.g. A382T and G294V, have genetic founder effects in certain geographic regions. However, such prevalence and founder effect have not been reported in Chinese. Methods Whole-exome sequencing (WES) was performed in 16 Chinese FALS patients, followed by Sanger sequencing for the TARDBP p.Gly298Ser mutation (G298S) in 798 SALS patients and 1,325 controls. Haplotype analysis using microsatellites flanking TARDBP was conducted in the G298S-carrying patients and noncarriers. The geographic distribution and phenotypic correlation of the TARDBP mutations reported worldwide were reviewed. Results WES detected the TARDBP G298S mutation in 8 FALS patients, and Sanger sequencing found additional 8 SALS cases, but no controls, carrying this mutation. All the 16 cases came from Southern China, and 7 of these patients shared the 117-286-257-145-246-270 allele for the D1S2736-D1S1151-D1S2667-D1S489-D1S434-D1S2697 markers, which was not found in the 92 non-carrier patients (0/92) (p < 0.0001) and 65 age-matched and neurologically normal individuals (0/65) (p < 0.0001). The A382T and G298S mutations were prevalent in Europeans and Eastern Asians, respectively. Additionally, carriers for the M337V mutation are dominated by bulbar onset with a long survival, whereas those for G298S are dominated by limb onset with a short survival. Conclusions Some prevalent TARDBP mutations are distributed in a geographic pattern and related to clinical profiles. TARDBP G298S mutation is a founder mutation in the Southern Chinese ALS population.

Evaluating the contribution of the gene TARDBP in Italian patients with amyotrophic lateral sclerosis

“…In our patients this variant was associated with later onset, shorter disease duration (Figure 1b) and more frequent bulbar onset with respect to other mutations, confirming previously reported findings in Chinese patients in which the p.G294V variant was the most frequent TARDBP mutation [28]. In particular, the high prevalence of bulbar onset appears to be a peculiar feature, being observed in 71% of our series and in 66% of those described in the literature [18,27,29].…”

Novel CSF Biomarkers Tracking Autoimmune Inflammatory and Neurodegenerative Aspects of CNS Diseases

“…TDP-43, encoded by the TARDBP gene, is the major aggregated protein involved in the formation of the characteristic inclusions, especially in its hyperphosphorylated and ubiquitin-bound form, in the brains of patients with ubiquitin-positive frontotemporal lobar degeneration (FTLD-U) and or ALS [141]. More than 50 mutations in the TARDBP gene have been identified across the FTD/ALS spectrum [143,144].…”