Email

zachary.castles@bcm.edu

Positions

PhD Student

Department of Molecular and Human Genetics
Genetics & Genomics Program
Baylor College of Medicine
Houston, Texas United States

Education

BS from Texas A&M University

05/2023 - College Station, Texas United States

Genetics, Bioinformatics

Professional Statement

Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder characterized by progressive muscle weakness and wasting, as well as several non-muscular complications such as cardiac, gastrointestinal and sleep abnormalities. DM1 is caused by a CTG trinucleotide repeat expansion in the 3’ untranslated region of the gene DMPK. Compared to a healthy range of 5-38 repeats, affected individuals can possess repeat lengths of 50 to more than 4000 in cases of congenital DM1. The mutant allele is transcribed into an RNA with long stretches of CUG repeats (CUGexp RNA) that forms large double-stranded hairpins and remains in the nucleus, unable to be efficiently exported. The CUGexp RNAs then bind to proteins, forming ribonucleoprotein complexes (RNPs) that accumulate as foci. The loss-of-function of sequestered RNA binding proteins, such as the Muscleblind-like (MBNL) family of splicing regulators, is a primary contributor to DM1 pathogenesis. However, little is known about the composition of the CUGexp RNP, and the mechanisms of its toxicity in DM1 pathology are unclear.
My project focuses on characterization of the CUGexp RNP foci— what proteins and RNAs are interacting at the foci, and what is their role in DM1 pathology? What are the mechanisms and factors involved in foci assembly? To approach this, I am utilizing proximity labeling with mass spectrometry and RNAseq to establish a molecular profile of the RNP. Ultimately, this work will enable the identification of proteins and RNAs that may have a critical function in RNP homeostasis and/or DM1 pathology, potentially revealing novel targets for future study and therapeutic application.

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