Molecular Characterization of Calreticulin Mutants Implicated in Sudden Unexplained Death

• Author / Creator

  Vega, Hector

• Sudden unexplained death (SUD) is a term used when comprehensive medical examination and autopsy fail to find a conclusive cause of sudden death. In cases of SUD, post-mortem molecular and genetic evaluation methods have helped identify ion channel abnormalities leading to arrhythmias as cause. However, many cases of SUD remain unexplained by ion channel mutation evaluation.
  Using whole exome sequencing (WES) analysis, followed by strategic variant filtration, several mutations in the calreticulin gene (CALR) have been identified in cases of SUD. One of these mutations leads to an ultra-rare frame-shift in CALR, encoding a truncated mutant protein, CALR376fs. CALR is an endoplasmic reticulum (ER) Ca2+-binding protein and molecular chaperone for proper folding, assembly, and retention of secreted and membrane proteins, among several other functions. The involvement of CALR mutants in the SUD phenotype is puzzling and the mechanism is unknown.
  Molecular characterization of the CALR mutants compared to wild-type protein was performed, with focus on CALR376fs. It was found that the mutant proteins were folded different compared to wild-type CALR. Further analysis of CALR376fs indicated that it was also highly degraded and had impaired chaperone function. Traffic to the plasma membrane and activity of a Ca2+ ion channel linked to SUD has recently been found to be higher in presence of CALR376fs compared to wild-type protein. The present suggests that altered structure, decrease in abundance, and impaired chaperone function of CALR376fs lead to a defect in ER quality control and higher activity of a Ca2+ ion channel likely to cause cardiac arrhythmia and SUD.

• Subjects / Keywords

  • Sudden unexplained death
  • 376 frame shift
  • Calreticulin
  • Mutants

• Graduation date

  Fall 2018

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R3T727X9T

• License

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