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

Abstract

BackgroundTARDBP mutations have been reported in patients with amyotrophic lateral sclerosis (ALS) in different populations except Chinese. The present aim is to investigate the association between TARDBP mutations and Chinese patients with ALS.Methods71 SALS patients and 5 FALS families with non-SOD1 mutations were screened for TARDBP mutations via direct sequencing.ResultsA 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).ConclusionsThe present data have extended the spectrum of TARDBP mutations and polymorphisms, and supported the pathological role of TDP-43 in Chinese ALS patients.

FTD and ALS: A Tale of Two Diseases

“…No variants were found in the cases of AD and PD while 7% of the investigated fALS and 0.5% of the investigated sALS did show mutations (including the two novel N352T and G384R) [218]. Recently TDP-43 was also screened in a cohort of Chinese extraction showing association between TDP-43 mutations and ALS; further screening is necessary to assess better the frequency and penetrance of TDP-43 mutations in Chinese ALS patients [219]. For completeness, a summary on the known mutations in TDP-43 and possible related pathogenic phenotypic effects are reviewed in [220].…”

Absence of Mutations in Exon 6 of the TARDBP Gene in 207 Chinese Patients with Sporadic Amyotrohic Lateral Sclerosis

“…In different Chinese populations,four substitution variants, p.S292N [6], p.G298S [10], p.M337V and p.N378D [8] were previously found in FALS subjects and four variants, S292N, G348V, A366A [3] and p.N378S [11] were detected in SALS cases. Those TARDBP variants are located in exon 6, but their pathological role has not yet been established because of small sample size of these studies.…”

“…The coding region of TARDBP exon 6 was analyzed using primer combinations based on TARDBP intronic sequences [6] PCR was carried out by mixing 20 pmol of each primers and 20 ng of genomic DNA template with 1.25u TaKaRa Taq, 5 µl 10×PCR Buffer (Mg 2+ Plus), and 4 µl 2.5 mM dNTP Mixture (Millipore Chemicon) in a final volume of 25 µL. The PCR was carried out using a BIOMETRA amplification system at 94°C for 2 min then 35 cycles of 94°C for 30 s, 63°C for 45 s and 72°C for 80 s. After a final elongation step at 72°C for 10 s, PCR products were stored at 4°C and run on ABI 3730 Automated DNA Sequencer according to previously published methods [7].…”

Novel TARDBP Sequence Variant and C9ORF72 Repeat Expansion in a Family With Frontotemporal Dementia

“…The same residue, p.Ser292, has previously been linked to Chinese patients with familial and sporadic ALS carrying a likely pathogenic missense mutation p.Ser292Asn (c.875G>A). 7,8 Interestingly, both patients with the p.Ser292del of TARDBP also carried the C9ORF72 expansion. The repeat expansion has been found to be the most common cause of familial FTLD and ALS, 1 and it is assumed as the disease causing mutation also in our siblings.…”