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A Novel Mutation of SMAD3 Identified in a Chinese Family with Aneurysms-Osteoarthritis Syndrome.

Zhang W, Zhou M, Liu C, Liu C, Qiao T, Huang D, Ran F, Wang W, Liu C, Liu Z - Biomed Res Int (2015)

Bottom Line: Previous studies have demonstrated that mutations in SMAD3, a key regulator of TGF-β signal transduction, contribute to AOS.A novel SMAD3 mutation, c.266G>A (p.C89Y), was identified and cosegregated with the affected individuals in this family.Our finding expands the mutation spectrum of SMAD3 gene and further strengthens the connection between the presence of aneurysms-osteoarthritis phenotype and SMAD3 mutations, which facilitates the understanding of the genotype-phenotype correlation of AOS.

View Article: PubMed Central - PubMed

Affiliation: Department of Vascular Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu 210008, China.

ABSTRACT
Aneurysms-osteoarthritis syndrome (AOS) is a recently delineated autosomal dominant disorder characterized by aneurysms, dissections, and tortuosity throughout the arterial tree in association with early onset osteoarthritis, mild craniofacial features, and skeletal and cutaneous anomalies. Previous studies have demonstrated that mutations in SMAD3, a key regulator of TGF-β signal transduction, contribute to AOS. Here, we investigated a family of three generations affected by AOS. A novel SMAD3 mutation, c.266G>A (p.C89Y), was identified and cosegregated with the affected individuals in this family. Our finding expands the mutation spectrum of SMAD3 gene and further strengthens the connection between the presence of aneurysms-osteoarthritis phenotype and SMAD3 mutations, which facilitates the understanding of the genotype-phenotype correlation of AOS.

No MeSH data available.


Related in: MedlinePlus

Mutation and bioinformatics analysis. (a) Sequencing results of the SMAD3 mutation. Sequence chromatogram indicates a G to A transition of nucleotide 266, resulting in a transformation of Cysteine into Tyrosine at amino acid position 89. (b) Sequence alignment of SMAD3 protein shows highly conserved amino acid Cysteine across species.
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fig2: Mutation and bioinformatics analysis. (a) Sequencing results of the SMAD3 mutation. Sequence chromatogram indicates a G to A transition of nucleotide 266, resulting in a transformation of Cysteine into Tyrosine at amino acid position 89. (b) Sequence alignment of SMAD3 protein shows highly conserved amino acid Cysteine across species.

Mentions: SMAD3 screening identified a heterozygous substitution of guanine to adenine at nucleotide 266 in the coding sequence of exon 2 (c.266G>A), in individuals II-1 and III-1 (Figure 2(a)). This variant resulted in a transformation of Cysteine into Tyrosine at amino acid position 89 (p.Cys89Tyr). It was not present in the unaffected individuals of the pedigree or in the 100 controls. Furthermore, this variant was not annotated in major databases, such as the Exome Sequencing Project, 1000 Genome, and dbSNP139. The altered amino acid is highly conserved across species (Figure 2(b)). Three programs for analyzing protein functions, PolyPhen2, SIFT, and MutationTaster, predicted that the p.C89Y variants are possibly damaging and disease causing, respectively. All three different algorithm based bioinformatics programs yield a consistent result of detrimental effect of the variant, suggesting that the site (C89) plays pivotal roles in the function of SMAD3.


A Novel Mutation of SMAD3 Identified in a Chinese Family with Aneurysms-Osteoarthritis Syndrome.

Zhang W, Zhou M, Liu C, Liu C, Qiao T, Huang D, Ran F, Wang W, Liu C, Liu Z - Biomed Res Int (2015)

Mutation and bioinformatics analysis. (a) Sequencing results of the SMAD3 mutation. Sequence chromatogram indicates a G to A transition of nucleotide 266, resulting in a transformation of Cysteine into Tyrosine at amino acid position 89. (b) Sequence alignment of SMAD3 protein shows highly conserved amino acid Cysteine across species.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4499615&req=5

fig2: Mutation and bioinformatics analysis. (a) Sequencing results of the SMAD3 mutation. Sequence chromatogram indicates a G to A transition of nucleotide 266, resulting in a transformation of Cysteine into Tyrosine at amino acid position 89. (b) Sequence alignment of SMAD3 protein shows highly conserved amino acid Cysteine across species.
Mentions: SMAD3 screening identified a heterozygous substitution of guanine to adenine at nucleotide 266 in the coding sequence of exon 2 (c.266G>A), in individuals II-1 and III-1 (Figure 2(a)). This variant resulted in a transformation of Cysteine into Tyrosine at amino acid position 89 (p.Cys89Tyr). It was not present in the unaffected individuals of the pedigree or in the 100 controls. Furthermore, this variant was not annotated in major databases, such as the Exome Sequencing Project, 1000 Genome, and dbSNP139. The altered amino acid is highly conserved across species (Figure 2(b)). Three programs for analyzing protein functions, PolyPhen2, SIFT, and MutationTaster, predicted that the p.C89Y variants are possibly damaging and disease causing, respectively. All three different algorithm based bioinformatics programs yield a consistent result of detrimental effect of the variant, suggesting that the site (C89) plays pivotal roles in the function of SMAD3.

Bottom Line: Previous studies have demonstrated that mutations in SMAD3, a key regulator of TGF-β signal transduction, contribute to AOS.A novel SMAD3 mutation, c.266G>A (p.C89Y), was identified and cosegregated with the affected individuals in this family.Our finding expands the mutation spectrum of SMAD3 gene and further strengthens the connection between the presence of aneurysms-osteoarthritis phenotype and SMAD3 mutations, which facilitates the understanding of the genotype-phenotype correlation of AOS.

View Article: PubMed Central - PubMed

Affiliation: Department of Vascular Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing, Jiangsu 210008, China.

ABSTRACT
Aneurysms-osteoarthritis syndrome (AOS) is a recently delineated autosomal dominant disorder characterized by aneurysms, dissections, and tortuosity throughout the arterial tree in association with early onset osteoarthritis, mild craniofacial features, and skeletal and cutaneous anomalies. Previous studies have demonstrated that mutations in SMAD3, a key regulator of TGF-β signal transduction, contribute to AOS. Here, we investigated a family of three generations affected by AOS. A novel SMAD3 mutation, c.266G>A (p.C89Y), was identified and cosegregated with the affected individuals in this family. Our finding expands the mutation spectrum of SMAD3 gene and further strengthens the connection between the presence of aneurysms-osteoarthritis phenotype and SMAD3 mutations, which facilitates the understanding of the genotype-phenotype correlation of AOS.

No MeSH data available.


Related in: MedlinePlus