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Identification and functional analysis of a new putative caveolin-3 variant found in a patient with sudden unexplained death.

Lariccia V, Nasti AA, Alessandrini F, Pesaresi M, Gratteri S, Tagliabracci A, Amoroso S - J. Biomed. Sci. (2014)

Bottom Line: Here we characterized a new putative Cav-3 variant, Cav-3 V82I, found in a patient with SCD.In heterologous systems Cav-3 V82I was expressed at significantly higher level than Cav-3 WT and accumulated within the cells.Cells expressing Cav-3 V82I exhibited a decreased activation of extracellular-signal-regulated kinases (ERKs) and were more vulnerable to sub-lethal osmotic stress.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biomedical Sciences and Public Health, School of Medicine, University "Politecnica delle Marche", Ancona, Italy. s.amoroso@univpm.it.

ABSTRACT

Background: Sudden cardiac death (SCD) is the clinical outcome of a lethal arrhythmia that can develop on the background of unrecognized channelopathies or cardiomyopathies. Several susceptibility genes have been identified for the congenital forms of these cardiac diseases, including caveolin-3 (Cav-3) gene. In the heart Cav-3 is the main component of caveolae, plasma membrane domains that regulate multiple cellular processes highly relevant for cardiac excitability, such as trafficking, calcium homeostasis, signal transduction and cellular response to injury. Here we characterized a new putative Cav-3 variant, Cav-3 V82I, found in a patient with SCD.

Results: In heterologous systems Cav-3 V82I was expressed at significantly higher level than Cav-3 WT and accumulated within the cells. Cells expressing Cav-3 V82I exhibited a decreased activation of extracellular-signal-regulated kinases (ERKs) and were more vulnerable to sub-lethal osmotic stress.

Conclusion: Considering that abnormal loss of myocytes can play a mechanistic role in lethal cardiac diseases, we suggest that the detrimental effect of Cav-3 V82I variant on cell viability may participate in determining the susceptibility to cardiac death.

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Related in: MedlinePlus

Caveolin-3 topological domains and localization of the V82I variation identified in LQTS patient. (a) Schematic topological organization of the caveolin-3 protein. Numbers above the line indicate amino acid residues in caveolin-3 protein sequence that define four domains (23): N-terminal (aa 1–53), scaffolding (aa 54–73), transmembrane (aa 74–106) and C-terminal (aa 107–151). V82I mutation affects a residue within the transmembrane domain. (b) Sequence alignment of caveolin-3 protein of the indicated vertebrates is shown. V82I mutation modifies a conserved amino acids in caveolin-3.
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Figure 1: Caveolin-3 topological domains and localization of the V82I variation identified in LQTS patient. (a) Schematic topological organization of the caveolin-3 protein. Numbers above the line indicate amino acid residues in caveolin-3 protein sequence that define four domains (23): N-terminal (aa 1–53), scaffolding (aa 54–73), transmembrane (aa 74–106) and C-terminal (aa 107–151). V82I mutation affects a residue within the transmembrane domain. (b) Sequence alignment of caveolin-3 protein of the indicated vertebrates is shown. V82I mutation modifies a conserved amino acids in caveolin-3.

Mentions: Sequencing analysis of CAV3 gene in 50 probands with suspected or diagnosed LQTS identified 9 single nucleotide variations (SNVs), 3 on the exon 1 amplicon and 6 on the exon 2 amplicon. Five SNVs were localized in the flanking region of exon 1 and exon 2 and were not considered in this study. The remaining four SNVs (C27T corresponding to SNP rs1974763, C99T to rs1008642, T123C to rs13087941 and G244T to rs112626848) were found in the coding region of the CAV3 gene; three of them (rs1974763, rs1008642 and rs13087941) were synonymous mutations with no pathogenic implications; instead rs112626848 was heterozygous missense mutation at nucleotide 244 (G > A) (Additional file1) leading to amino acid change, valine to isoleucine, at codon 82 (V82I), involving a residue conserved across several species in the transmembrane domain (Figure 1 and[12]).


Identification and functional analysis of a new putative caveolin-3 variant found in a patient with sudden unexplained death.

Lariccia V, Nasti AA, Alessandrini F, Pesaresi M, Gratteri S, Tagliabracci A, Amoroso S - J. Biomed. Sci. (2014)

Caveolin-3 topological domains and localization of the V82I variation identified in LQTS patient. (a) Schematic topological organization of the caveolin-3 protein. Numbers above the line indicate amino acid residues in caveolin-3 protein sequence that define four domains (23): N-terminal (aa 1–53), scaffolding (aa 54–73), transmembrane (aa 74–106) and C-terminal (aa 107–151). V82I mutation affects a residue within the transmembrane domain. (b) Sequence alignment of caveolin-3 protein of the indicated vertebrates is shown. V82I mutation modifies a conserved amino acids in caveolin-3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4109384&req=5

Figure 1: Caveolin-3 topological domains and localization of the V82I variation identified in LQTS patient. (a) Schematic topological organization of the caveolin-3 protein. Numbers above the line indicate amino acid residues in caveolin-3 protein sequence that define four domains (23): N-terminal (aa 1–53), scaffolding (aa 54–73), transmembrane (aa 74–106) and C-terminal (aa 107–151). V82I mutation affects a residue within the transmembrane domain. (b) Sequence alignment of caveolin-3 protein of the indicated vertebrates is shown. V82I mutation modifies a conserved amino acids in caveolin-3.
Mentions: Sequencing analysis of CAV3 gene in 50 probands with suspected or diagnosed LQTS identified 9 single nucleotide variations (SNVs), 3 on the exon 1 amplicon and 6 on the exon 2 amplicon. Five SNVs were localized in the flanking region of exon 1 and exon 2 and were not considered in this study. The remaining four SNVs (C27T corresponding to SNP rs1974763, C99T to rs1008642, T123C to rs13087941 and G244T to rs112626848) were found in the coding region of the CAV3 gene; three of them (rs1974763, rs1008642 and rs13087941) were synonymous mutations with no pathogenic implications; instead rs112626848 was heterozygous missense mutation at nucleotide 244 (G > A) (Additional file1) leading to amino acid change, valine to isoleucine, at codon 82 (V82I), involving a residue conserved across several species in the transmembrane domain (Figure 1 and[12]).

Bottom Line: Here we characterized a new putative Cav-3 variant, Cav-3 V82I, found in a patient with SCD.In heterologous systems Cav-3 V82I was expressed at significantly higher level than Cav-3 WT and accumulated within the cells.Cells expressing Cav-3 V82I exhibited a decreased activation of extracellular-signal-regulated kinases (ERKs) and were more vulnerable to sub-lethal osmotic stress.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Biomedical Sciences and Public Health, School of Medicine, University "Politecnica delle Marche", Ancona, Italy. s.amoroso@univpm.it.

ABSTRACT

Background: Sudden cardiac death (SCD) is the clinical outcome of a lethal arrhythmia that can develop on the background of unrecognized channelopathies or cardiomyopathies. Several susceptibility genes have been identified for the congenital forms of these cardiac diseases, including caveolin-3 (Cav-3) gene. In the heart Cav-3 is the main component of caveolae, plasma membrane domains that regulate multiple cellular processes highly relevant for cardiac excitability, such as trafficking, calcium homeostasis, signal transduction and cellular response to injury. Here we characterized a new putative Cav-3 variant, Cav-3 V82I, found in a patient with SCD.

Results: In heterologous systems Cav-3 V82I was expressed at significantly higher level than Cav-3 WT and accumulated within the cells. Cells expressing Cav-3 V82I exhibited a decreased activation of extracellular-signal-regulated kinases (ERKs) and were more vulnerable to sub-lethal osmotic stress.

Conclusion: Considering that abnormal loss of myocytes can play a mechanistic role in lethal cardiac diseases, we suggest that the detrimental effect of Cav-3 V82I variant on cell viability may participate in determining the susceptibility to cardiac death.

Show MeSH
Related in: MedlinePlus