An RYR1 mutation associated with malignant hyperthermia is also associated with bleeding abnormalities

Area of Science:

• Genetics
• Pharmacology
• Physiology

Background:

• Malignant hyperthermia (MH) is a life-threatening disorder linked to RYR1 gene mutations.
• RYR1 mutations are primarily associated with muscle function, but RYR1 is also in smooth muscle.
• Bleeding abnormalities have been anecdotally reported in MH patients with RYR1 mutations.

Purpose of the Study:

• To investigate the frequency and molecular basis of bleeding abnormalities in individuals with RYR1 mutations.
• To explore the role of vascular smooth muscle cell function in RYR1-associated bleeding.

Main Methods:

• Analyzed bleeding scores in patients with specific RYR1 mutations and their relatives.
• Utilized knock-in mouse models (MHS RYR1Y522S) to study bleeding times.
• Examined calcium (Ca2+) spark activity and membrane potential in vascular smooth muscle cells.
• Assessed the effect of dantrolene and ryanodine on bleeding and Ca2+ sparks.

Main Results:

• Specific RYR1 mutations correlated with increased bleeding scores in patients.
• MHS RYR1Y522S mice exhibited prolonged bleeding times compared to wild-type.
• Vascular smooth muscle cells from MHS RYR1Y522S mice showed increased Ca2+ sparks and altered membrane potential.
• Dantrolene treatment reversed bleeding defects in mice and one patient, and blocked Ca2+ sparks.

Conclusions:

• RYR1 mutations can lead to prolonged bleeding by disrupting vascular smooth muscle cell function.
• Altered Ca2+ handling in smooth muscle cells contributes to the bleeding phenotype.
• Dantrolene shows therapeutic potential for treating RYR1-associated bleeding disorders.