# Decoding Myosin-3 mutational hotspots: Linking deleterious variants to Duchenne muscular dystrophy severity and psychiatric comorbidities

## TL;DR

This study explores how mutations in the MYH3 gene, which encodes Myosin-3, may worsen Duchenne muscular dystrophy and contribute to psychiatric issues.

## Contribution

The study identifies deleterious MYH3 mutations that may exacerbate DMD severity and potentially link to psychiatric comorbidities.

## Key findings

- 80 out of 89 analyzed MYH3 missense mutations were predicted to be pathogenic.
- Five mutations (G182A, R244C, R244H, H285Y, N483S) occur in evolutionarily conserved regions of Myosin-3.
- The G182A mutation affects the ATP-binding site and may impair myosin activity, potentially worsening DMD.

## Abstract

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder primarily caused by mutations in the dystrophin gene, leading to progressive muscle degeneration. While the loss of dystrophin is central to DMD pathogenesis, impaired muscle regeneration further exacerbates disease severity. As MYH3-encoding Myosin-3 is involved in muscle development and regeneration, we examined how it could be added to the list of possible contributors to DMD pathology. This study employed various computational tools such as PolyPhen-2, SIFT, and I-Mutant to analyze 486 MYH3 missense mutations and predict the structural and functional implications. We discovered 89 deleterious substitutions, of which 80 were pathogenic. Of these, 45 mutations were identified as likely to pathogenically alter Myosin-3 solubility, and 5 (G182A, R244C, R244H, H285Y, N483S) fell within evolutionarily conserved regions. The mutant G182A is of particular interest as it lies within the ATP-binding site, which may lead to an impairment of energy-dependent myosin activity. These mutations likely impair muscle regeneration, potentially intensifying the severity of dystrophy. Furthermore, we hypothesize that these functional deficiencies may not be limited to muscle pathogenesis and could be related to the development of neuropsychiatric comorbidities observed in DMD, although this remains to be experimentally confirmed. Our results emphasize the relevance of Myosin-3 in the pathogenesis of DMD and the importance of combined research on neuromuscular and psychiatric aspects to improve therapeutic approaches.