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

Xiong HL, Wang JY, Sun YM, Wu JJ, Chen Y, Qiao K, Zheng QJ, Zhao GX, Wu ZY - BMC Med. Genet. (2010)

Bottom Line: This variation was not found in 200 unrelated control subjects.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, PR China.

ABSTRACT

Background: TARDBP 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.

Methods: 71 SALS patients and 5 FALS families with non-SOD1 mutations were screened for TARDBP mutations via direct sequencing.

Results: 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).

Conclusions: The present data have extended the spectrum of TARDBP mutations and polymorphisms, and supported the pathological role of TDP-43 in Chinese ALS patients.

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Chromatogram of Ser292Asn (A) and conservation of Ser292Asn in different species (B).
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Figure 1: Chromatogram of Ser292Asn (A) and conservation of Ser292Asn in different species (B).

Mentions: After screening mutations of TARDBP in 5 FALS patients and 71 SALS patients, a heterozygous variation Ser292Asn (875G>A) which has not been reported previously was identified in a FALS patient. The chromatogram is shown in figure 1A. This variation was not found in 200 unrelated control subjects, reducing the likelihood that it represents a polymorphism. Moreover, a homology search of the TDP-43 protein in different species demonstrated that this variation was highly conserved (figure 1B). At the same time, the program SIFT (Sorting Intolerant From Tolerant) [23] has been applied to predict whether this sequence change could affect protein function, and it was predicted to be deleterious to protein function with SIFT-calculated probabilities of 0.00, thus Ser292Asn is a novel mutation and most probably a pathogenic one.


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

Xiong HL, Wang JY, Sun YM, Wu JJ, Chen Y, Qiao K, Zheng QJ, Zhao GX, Wu ZY - BMC Med. Genet. (2010)

Chromatogram of Ser292Asn (A) and conservation of Ser292Asn in different species (B).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2821387&req=5

Figure 1: Chromatogram of Ser292Asn (A) and conservation of Ser292Asn in different species (B).
Mentions: After screening mutations of TARDBP in 5 FALS patients and 71 SALS patients, a heterozygous variation Ser292Asn (875G>A) which has not been reported previously was identified in a FALS patient. The chromatogram is shown in figure 1A. This variation was not found in 200 unrelated control subjects, reducing the likelihood that it represents a polymorphism. Moreover, a homology search of the TDP-43 protein in different species demonstrated that this variation was highly conserved (figure 1B). At the same time, the program SIFT (Sorting Intolerant From Tolerant) [23] has been applied to predict whether this sequence change could affect protein function, and it was predicted to be deleterious to protein function with SIFT-calculated probabilities of 0.00, thus Ser292Asn is a novel mutation and most probably a pathogenic one.

Bottom Line: This variation was not found in 200 unrelated control subjects.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology and Institute of Neurology, Huashan Hospital, State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, 12 Wulumuqi Zhong Road, Shanghai 200040, PR China.

ABSTRACT

Background: TARDBP 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.

Methods: 71 SALS patients and 5 FALS families with non-SOD1 mutations were screened for TARDBP mutations via direct sequencing.

Results: 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).

Conclusions: The present data have extended the spectrum of TARDBP mutations and polymorphisms, and supported the pathological role of TDP-43 in Chinese ALS patients.

Show MeSH
Related in: MedlinePlus