A novel gene, TARDBP, and the protein it encodes can predict glioma patient prognosis and establish a prediction model.

BACKGROUND: TDP-43 (43-kD transactive response DNA-binding protein) is a DNA-/RNA-binding protein that plays an important role in several nervous system diseases, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Whether it plays an important role in glioma patients is unknown. METHODS: Datasets were downloaded from the Chinese Glioma Genome Atlas (CGGA) website ( http://www.cgga.org.cn/ ). Cox survival analysis was performed to determine the relationship between TARDBP gene expression and the overall survival of glioma patients. GO analyses were performed to determine the biological functions of the TARDBP gene. Finally, we used PRS type, age, grade, IDH mutation status, 1p/19q codeletion status, and expression value of the TARDBP gene to construct a prediction model. With this model, we can predict patients' 1-, 2-, 3-, 5-, and 10-year survival rates. RESULTS: The TARDBP gene plays an important role in glioma patients. The expression of the TARDBP gene has a significant correlation with glioma patient survival. We also constructed an ideal prediction model. CONCLUSION: Our findings suggest that the TARDBP gene and the protein it encodes play important roles in glioma patients. The expression of the TARDBP gene has a significant correlation with the overall survival of glioma patients.

A patient carrying a heterozygous p.Asn267Ser TARDBP missense mutation diagnosed as ALS and only involving lower motor neurons.

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease involving upper motor neurons (UMN) and lower motor neurons (LMN), which can be caused by mutations of pathogenic genes such as superoxide dismutase 1 (SOD1), sarcoma fusion (FUS), and TAR-DNA binding protein (TARBDP/TDP-43). Among these pathogenic genes, TARBDP mutation accounts for approximately 1% of sporadic ALS (sALS). The clinical phenotype of ALS is heterogeneous owing to different mutant genes and sites. Here, we report a case of sALS from China, the pathogenic site (c.800A > G) of TARDBP in this patient was identified by whole-exome sequencing. But his clinical symptoms involve only the LMN, presented with progressive limb weakness, and dyspnea, without obvious limb muscle atrophy. We considered this patient as a possible LMN-dominant ALS variant and this report further explores the genotype-phenotype correlations of ALS10. Furthermore, interestingly, the pathogenic site in this person was previously reported in a Parkinson's disease (PD) patient and frontotemporal dementia (FTD) patient. Our findings illustrate the clinical heterogeneity and the types of diseases which carry p.Asn267Ser TDP-43 mutation were broadened furtherly. Meanwhile, considering that the range of neurodegenerative diseases associated with this mutant site may be expanding, the mechanism of different neurodegenerative changes mediated by the same pathogenic site still needs to be further studied.

Clinical Characteristics and Gene Mutations Analysis of a ALS10 Chinese Han Family / 中山大学学报(医学科学版)

[Objective] To explore the clinical features,genetic characters in family amyotrophic lateral sclerosis (ALS10)patients.[Methods] TARDBP gene mutations in Chinese Han family patients with ALS10 diagnosed by the First Affiliated Hospital of Sun Yat-sen University in 2013 was screened by high-throughput sequencing.[Results] There were 5 patients in three generations in this family.The initial symptoms in all affected members were distal limb muscle weakness and dystrophy at their 50 age.With a rapid progression of symptoms about 8 to 18 months.A homozygous missense mutation (c.892G＞A) were detected in TARDBP gene exon 6 of the propositus,as well as the other three family members without any clinical symptoms.[Conclusion] ALS10 is a faster progressive and shorter survival time FALS.Since there was no effective treatment in ALS10,hereditary consultation and prenatal diagnosis play an important role in disease prevention and hereditary.

Two distinct clinical features and cognitive impairment in amyotrophic lateral sclerosis patients with TARDBP gene mutations in the Chinese population.

Mutations in the TARDBP gene have been identified as a major causative factor in amyotrophic lateral sclerosis (ALS). However, few reports have analyzed the relationship of genotype-phenotype, especially in Chinese ALS patients. Our study investigated the presence and frequency of TARDBP mutations in Chinese patients with ALS. Additionally, we investigated correlations among clinical features and TARDBP gene mutations in a large ALS family with the p.M337 V mutation and one sporadic ALS (SALS) patient with the p.S393 L mutation. The pedigree with the p.M337 V mutation showed variable clinical features with a long lifespan, particularly cognitive impairment. One patient carrying the p.S393 L mutation experienced ALS with cognitive impairment; the patient also had a family history of frontotemporal dementia (FTD). This is the first report of detailed genetic and clinical characterizations of the TARDBP gene in a Chinese population. This research is also the first to demonstrate that the p.M337 V and the p.S393 L mutations are related to cognitive impairment in ALS patients. The mutation frequency of TARDBP was 5.6% in Chinese, SOD1-negative familial ALS (FALS), which was much higher than that reported in previous studies conducted with Caucasian populations, whereas the TARDBP mutation frequency was lower in the Chinese population with regard to SALS patients. Our results emphasize the importance of the genetic and clinical characterization of TARDBP mutations in ALS, which allows us to understand the genotype-phenotype relationship and relative frequencies in different populations.