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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Three pedigrees (M23969, M13948, and M31584) carried SOD1 mutations, and the corresponding forward sequencing chromatogram of mutations in both probands and controls is shown.The arrow on the pedigree represents the proband. The circles denote females, and squares denote males. Affected individuals are noted by black symbols and unaffected individuals are noted by blank symbols. Carriers are noted by a black dot. Deceased individuals are noted by a slash symbol. M23225, M18301 and M23362 represent forward sequencing chromatogram of sALS patients with SOD1 mutations. M23969:c.335G>A (p.C111Y); M13948:c.304G>A (p.D101N); M31584:c.305A>G (p.D101G); M23225:c.260A>G (p.N86S); M18301:c.335G>A (p.C111Y); M23362:c.263T>C (p.V87A).
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f1: Three pedigrees (M23969, M13948, and M31584) carried SOD1 mutations, and the corresponding forward sequencing chromatogram of mutations in both probands and controls is shown.The arrow on the pedigree represents the proband. The circles denote females, and squares denote males. Affected individuals are noted by black symbols and unaffected individuals are noted by blank symbols. Carriers are noted by a black dot. Deceased individuals are noted by a slash symbol. M23225, M18301 and M23362 represent forward sequencing chromatogram of sALS patients with SOD1 mutations. M23969:c.335G>A (p.C111Y); M13948:c.304G>A (p.D101N); M31584:c.305A>G (p.D101G); M23225:c.260A>G (p.N86S); M18301:c.335G>A (p.C111Y); M23362:c.263T>C (p.V87A).

Mentions: The c.335G>A, p.C111Y mutation was identified in a fALS proband (Fig. 1 M23969: I2). At age 68, she developed a slowly progressive distal weakness in her upper left limb, and one month later, the weakness spread to the lower left limb, while fasciculation and atrophy in the upper left limb were observed. A neurological examination revealed signs of upper motor neuron (UMN) damage, and an electromyogram indicated the presence of generalized chronic progressive neurogenic damage. Her daughter (Fig. 1 M23969: II4) developed progressive weakness in her lower left limb at age 46 and quickly developed weakness, dysarthria and dysphagia in all four extremities within one year. She then died of respiratory failure after18 months. Although her daughter carried the same mutation, she had an earlier age of onset and a seemingly worse clinical phenotype than her mother. Her sons did not carry this mutation or share this clinical phenotype.


Screening of SOD1 , FUS and TARDBP genes in patients with amyotrophic lateral sclerosis in central-southern China
Three pedigrees (M23969, M13948, and M31584) carried SOD1 mutations, and the corresponding forward sequencing chromatogram of mutations in both probands and controls is shown.The arrow on the pedigree represents the proband. The circles denote females, and squares denote males. Affected individuals are noted by black symbols and unaffected individuals are noted by blank symbols. Carriers are noted by a black dot. Deceased individuals are noted by a slash symbol. M23225, M18301 and M23362 represent forward sequencing chromatogram of sALS patients with SOD1 mutations. M23969:c.335G>A (p.C111Y); M13948:c.304G>A (p.D101N); M31584:c.305A>G (p.D101G); M23225:c.260A>G (p.N86S); M18301:c.335G>A (p.C111Y); M23362:c.263T>C (p.V87A).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5015023&req=5

f1: Three pedigrees (M23969, M13948, and M31584) carried SOD1 mutations, and the corresponding forward sequencing chromatogram of mutations in both probands and controls is shown.The arrow on the pedigree represents the proband. The circles denote females, and squares denote males. Affected individuals are noted by black symbols and unaffected individuals are noted by blank symbols. Carriers are noted by a black dot. Deceased individuals are noted by a slash symbol. M23225, M18301 and M23362 represent forward sequencing chromatogram of sALS patients with SOD1 mutations. M23969:c.335G>A (p.C111Y); M13948:c.304G>A (p.D101N); M31584:c.305A>G (p.D101G); M23225:c.260A>G (p.N86S); M18301:c.335G>A (p.C111Y); M23362:c.263T>C (p.V87A).
Mentions: The c.335G>A, p.C111Y mutation was identified in a fALS proband (Fig. 1 M23969: I2). At age 68, she developed a slowly progressive distal weakness in her upper left limb, and one month later, the weakness spread to the lower left limb, while fasciculation and atrophy in the upper left limb were observed. A neurological examination revealed signs of upper motor neuron (UMN) damage, and an electromyogram indicated the presence of generalized chronic progressive neurogenic damage. Her daughter (Fig. 1 M23969: II4) developed progressive weakness in her lower left limb at age 46 and quickly developed weakness, dysarthria and dysphagia in all four extremities within one year. She then died of respiratory failure after18 months. Although her daughter carried the same mutation, she had an earlier age of onset and a seemingly worse clinical phenotype than her mother. Her sons did not carry this mutation or share this clinical phenotype.

View Article: PubMed Central - PubMed

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.

No MeSH data available.