DOI
https://doi.org/10.25772/AM10-8830
Author ORCID Identifier
https://orcid.org/0009-0008-9781-1905
Defense Date
2024
Document Type
Thesis
Degree Name
Master of Science
Department
Human and Molecular Genetics
First Advisor
Nicholas Johnson
Second Advisor
Dana Lapato
Third Advisor
Swadesh Das
Abstract
Myotonic dystrophy type 1 (DM1) is a slowly progressive, multisystem disorder caused by a CTG repeat expansion in the DMPK 3’UTR that leads to global dysregulation of alternative splicing. The resulting decline in physical function is slow, and no reliable biomarkers exist for predicting disease progression; however, an RNA mis-splicing biomarker associated with weakness may have utility in predicting functional outcomes. Here we validate the Splice Index (SI) as a potential biomarker of DM1-associated strength and function. Muscle biopsies of the tibialis anterior were collected from DM1-affected individuals at baseline (n = 46) and 3-months (n = 34), along with measures of strength and physical function. RNA sequencing was used to derive the SI and was reliable across technical replicates. The SI had significant associations to measures of ankle dorsiflexion strength (r = -0.69), which improved when comparing the baseline SI to the 3-month ankle dorsiflexion strength (r = -0.78). Linear regression revealed that the combination of baseline ankle dorsiflexion strength and SI was predictive of strength at 3-months in our cohort (adjusted R2 = 0.83). These results indicate the SI can reliably capture the association of disease-specific RNA mis-splicing to physical strength and mobility and may be predictive of future function.
Rights
© Marina G. Provenzano
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
5-10-2024
Included in
Genetics Commons, Laboratory and Basic Science Research Commons, Molecular Genetics Commons, Musculoskeletal Diseases Commons, Translational Medical Research Commons