Unraveling Novel Pathogenic CAPN3 Variants in Limb-Girdle Muscular Dystrophy R1
Sukanya Banerjee and Bishan Dass Radotra*
Department of Histopathology, Post Graduate Institute of Medical Education and Research, Chandigarh-160012, India
Limb-Girdle Muscular Dystrophy R1 (LGMDR1) is an autosomal recessive neuromuscular disorder caused by mutations in the calpain-3 (CAPN3) gene, which encodes a calcium-dependent intracellular protease. Various pathogenic mutations have been reported to date, typically leading to weakness of the pelvic and shoulder girdle muscles. However, the clinical and pathological features of LGMDR1 are often heterogeneous and overlap with those of other LGMD subtypes, making a definitive molecular diagnosis essential for understanding the disease pathogenesis. Immunoblot analysis of calpain-3 protein revealed either complete or partial loss of expression in patients with LGMD. Additionally, multiple CAPN3 variants were identified and evaluated using in silico pathogenicity prediction tools. Alongside previously known mutations, Sanger sequencing also revealed novel pathogenic variants in the CAPN3 gene. Identification of genetic variants in LGMDR1 patients helps explore the mechanisms of disease pathogenesis and may support more accurate diagnosis and prognostication.
DOI: 10.29245/2572-9411/2025/1.1218a View / Download PdfCommentary: Tumor suppressor p53 regulates heat shock factor 1 protein degradation in Huntington’s disease
Rocio Gomez-Pastor.
Department of Neuroscience, University of Minnesota, School of Medicine, Minneapolis, MN, United States.
Huntington’s disease (HD) is a rare, inherited neurodegenerative disorder marked by progressive motor impairment, cognitive decline, and psychiatric disturbances. Increasing evidence implicates dysregulated cellular stress responses in HD pathogenesis, particularly involving the antagonistic interplay between the transcription factors p53 and heat shock factor 1 (HSF1)—key regulators of both cancer biology and neurodegeneration. This commentary highlights recent findings by Mansky et al., which uncover a novel mechanism whereby mutant huntingtin (mtHTT) stabilizes p53, triggering the degradation of HSF1 in striatal neurons. This mechanistic link offers new insight into how disrupted proteostasis drives neuronal vulnerability in HD, highlighting the p53–HSF1 axis as a promising therapeutic target. Additionally, we examine evidence that similar regulatory dynamics may contribute to other neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, suggesting a potentially conserved molecular pathway underlying neuronal degeneration in rare disorders. These findings underscore the therapeutic potential of modulating stress-responsive transcriptional networks to slow or prevent disease progression in HD and related conditions.
DOI: 10.29245/2572-9411/2025/1.1219 View / Download PdfVascular Ehlers-Danlos Syndrome: Current Understanding and Treatment Strategies
Reece M. Foehr1, Erik D. Foehr2*
1Saint Louis University, School of Medicine, Saint Louis, MO, USA
2Kin Therapeutics, Novato, CA, USA
Vascular Ehlers-Danlos Syndrome (vEDS) is a rare and severe subtype of Ehlers-Danlos Syndrome (EDS), a group of inherited disorders affecting connective tissue. Unlike other EDS subtypes primarily characterized by joint hypermobility and skin elasticity, vEDS is distinguished by its impact on the vascular system, posing a significant risk of life-threatening complications1. This review aims to provide a concise overview of vEDS, encompassing its genetic basis, clinical manifestations, diagnostic approaches, and current treatment strategies.
DOI: 10.29245/2572-9411/2025/1.1217 View / Download Pdf