The gene LMNA encodes the A-type lamins, vital components of a protein meshwork lining the inner nuclear membrane known as the nuclear lamina. Mutations in genes encoding several components of this meshwork result in a collection of diseases known as laminopathies, with the majority of these diseases due to LMNA mutations. There are at least 500 pathogenic mutations in LMNA that give rise to at least 16 clinically distinct phenotypes, the most for any human gene. The most common phenotypes associated with LMNA mutations are muscular dystrophy (LMNA-MD) and various cardiac diseases, most notably dilated cardiomyopathy. LMNA-MD is known to be extremely phenotypically variable, even among siblings with the same mutation. Family members can receive different clinical diagnoses or can exhibit variable age of symptom onset, phenotype severity, and rate of disease progression. This phenotypic variability has long been attributed to genetic background differences between individuals known as genetic modifiers. However, there has been limited identification of specific LMNA-MD modifier genes to date. Through collaboration with clinicians at UIHC and directly with patients, my research focuses on the identification of modifier genes in families where siblings present with the same LMNA mutation and variable disease severity. Using whole genome sequencing, we are able to identify potential genetic modifiers present only in severely affected siblings and functionally test the ability of these variants to enhance disease severity using modeling in Drosophila. Specifically, my research focuses on variants in the gene SMAD7 that lead to upregulation of the SMAD signaling pathway, as variants in other genes that cause upregulation of this pathway have previously been described as modifiers of other more common muscular dystrophies. The importance of identifying genetic modifiers should be underscored, as they can be used to stratify individuals in clinical trials, identify novel therapeutic targets, and improve predictions of prognosis and genetic counseling.

Publications:

Mohar NP, Cox EM, Adelizzi E, Moore SA, Mathews KD, Darbro BW, Wallrath LL. The Influence of a Genetic Variant in CCDC78 on LMNA-Associated Skeletal Muscle Disease. International Journal of Molecular Sciences. 2024; 25(9):4930. https://doi.org/10.3390/ijms25094930

Honors/Awards:

Pharmacological Sciences T32 Predoctoral Training Grant  (2023 - 2024)

Graduate Student Senate Travel Grant Recipient (2023) 

Midwest Drosophila Conference Outstanding Oral Presentation (2023)

Pharmacological Sciences T32 Predoctoral Training Grant  (2022 - 2023)