You are a researcher who studies the molecular structure of the ryanodine recept
ID: 54821 • Letter: Y
Question
You are a researcher who studies the molecular structure of the ryanodine receptor (RyR) proteins. You've discovered a mutation in the gene encoding RyR that is associated with early infant death. In order to study the mutation, you genetically engineer a laboratory mouse so that it expresses only this mutant form of the gene encoding the ryanodine receptor protein. The mutation interferes with the ability of the protein to open in response to calcium ion binding, but does not confer any other structural or functional changes. Write a paragraph describing the what you would predict would happen to contraction of skeletal and cardiac muscle in the mouse, and explaining why the mutation could be fatal in infants.
Explanation / Answer
Ryanodine receptors (RyR), named after a plant alakaloid ryanodine, are a family of intracellular calcium channels mostly present in excitable tissues like muscles and neurons. The major role of ryanodine receptor is to take part in various signaling pathways involving calcium release from intracellular organelles (sarcoplasmic reticulum). There are 3 mammalian isoforms of the ryanodine receptor.
The RYR2 ryanodine receptor isoform is responsible for the calcium-induced calcium release (CICR) in animal cells. CICR is a biological process in which calcium ions trigger calcium release from sarcoplasmic reticulum.
When an action potential depolarizes the cell membrane, voltage-gated Ca2+ channels (for e.g., L-type calcium channels) get activated and releases calcium. The resulting Ca2+ influx activates the ryanodine receptors present on the sarcoplasmic reticulum membrane, which causes the release of more calcium into the cytosol. Further, the higher levels of cytosolic calcium levels initiate the excitation-contraction coupling in cardiac muscles.
In the given case, most precisely, mutation occurred on the gene responsible for the encoding of RyR2 protein which further generated a damaged protein and consequently interferes in the calcium induced calcium release (in skeletal and cardiac muscle) and thus, inhibited the cascade of skeletal and cardiac muscle contraction.
When mutated, the gene produces damaged RyR2 protein which causes arrhythmias in mouse and ultimately leads to sudden death (Mathur et al., 2009).
Similarly in case of infants, the mutation leads to the generation of damaged RyR2 protein which interferes in the proper functioning of cardiac muscle contraction. In absence of contraction or due to abnormal contraction, a lethal polymorphic ventricular tachycardia may occur which may further leads to syncope or sudden death.
Above statements can be supported with the various studies which reported the role of RyR2 receptor in induction of lethal ventricular arrhythmias (Tester et al., 2007). Recently some researchers reported that mutation in RyR2 is a probable cause of sudden infant death syndrome (Napalitano, 2007 & Cheung et al., 2015).
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