Comprehensive Analysis of Mutations in the Skeletal Muscle Ryanodine Receptor (RyR1).
Abstract
General Abstract
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Patients born with mutations in the skeletal muscle ryanodine receptor (RyR1) suffer from
muscular dysfunction associated with significant morbidity. Previous research has elucidated the
pathophysiology of the disease and structure of the receptor, yet we are lacking in our understanding of
the relationship between specific mutations in correlation to specific clinical manifestations. Currently,
clinicians advise their patients to screen for RyR1 mutations yet when the results are returned
positive—clinicians fail to determine the outcome in regard to precautions and prognosis. A
comprehensive database, including all known RyR1 mutations documented in the literature and by
international collaborators, was created to study the link between specific mutations and its clinical
manifestations. In this project, the database has been utilized to identify specific regions in the receptor
that can be associated with significant morbidity.
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Scientific Abstract
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Mutations in the ryanodine receptor (RyR1) are associated with malignant hyperthermia (MH)
and RyR1-related myopathy. These mutations exhibit phenotypic and clinical variability, complicating
the ability to assign pathogenicity. While gene sequencing is widely available, it has become difficult
to determine whether or not variants are pathogenic. Over the past few decades, hundreds of patients
have been reported in the literature along with their RyR1 variants. Our goal was to comprehensively
review and organize all the clinical, genetic, and bioinformatics data from the literature and individual
testing centers into an easily searchable database. This would make it possible to identify features of
diseased and benign variants that can be used to predict outcome of unknown variants. Genetic and
clinical data were obtained from PubMed and international collaborators. All together, we identified
1094 unique variants from 2265 patients with clinical suspicion for RyR1-related myopathy or
malignant hyperthermia. The data was organized into a comprehensive, easily searchable database,
along with 255 bioinformatics related data points for each variant. The availability of an easily
searchable database that organizes genetic, clinical, bioinformatics, and structural data will help
clinicians and scientists diagnose and treat patients suffering from these conditions.
The database can be populated with data from different laboratories and incorporate highresolution
cryo-EM structural spatial localization information, in-vitro and ex-vivo functional data, and
patient clinical data. Eventually, it will help predict the functional effects of any RyR1 mutation and
will provide investigators with a powerful tool for understanding the pathophysiology of a specific
patient’s disease process and for designing personalized therapies.
Description
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Mentor: Professor Radhashree Maitra, Department of Biology
Permanent Link(s)
https://hdl.handle.net/20.500.12202/4357https://yulib002.mc.yu.edu/login?url=https://repository.yu.edu/handle/20.500.12202/4357
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