Juberg-Marsidi Syndrome: Exploring Its Causes.

SUMMARY Rare genetic diseases affect about 8% of the world's newborn population. Current technological advances in exome and genome sequencing of patients with suspected genetic syndromes enable genetic diagnosis. Yet, most rare diseases currently have no effective treatment, and many remain untreated because the functional follow-up into the pathogenesis lags. This proposal addresses a rare genetic condition, Juberg- Marsidi syndrome, which is caused by mutations in the gene that codes for the E3 ligase HUWE1. We are particularly interested in HUWE1 pathogenic variants, which result in severe craniofacial abnormalities. We determined that HUWE1 is a critical regulator of signal transmission through the fundamental molecular axis of the Shoc2-mediated extracellular signal-regulated kinases 1 and 2 (ERK1/2) signal pathway. Congenital mutations in the shoc2 gene cause the genetic disorder that presents with short stature, facial dysmorphia, cleft palate, and craniosynostosis. Based on this preliminary data, the central hypothesis of this proposal is that hereditary HUWE1 mutations cause cranial malformations by altering the capacity of HUWE1 to regulate ERK1/2 signal transmission via the Shoc2 complex, thereby affecting cartilage and bone development. We will test our hypothesis by pursuing two Specific Aims: 1) Determine how HUWE1-linked Juberg-Marsidi syndrome variants impact ERK1/2 activity, and 2) Determine whether neural-crest-derived cranial tissues are altered in zebrafish larvae carrying HUWE1 pathogenic variants. The proposed work will establish preliminary data critical for successful future studies focused on the strategies for therapeutic approaches addressing HUWE1- linked abnormalities. We will use zebrafish to investigate the in vivo effect of HUWE1 gene editing on the early stages of cranial morphogenesis. Zebrafish offer distinct advantages for craniofacial studies, including their transparency and rapid external development. The proposed research applies our unique expertise and research capacity, integrating studies with zebrafish and biochemical methodologies. The studies proposed here are poised to uncover a novel mechanistic effect of HUWE1 mutations on signaling outcomes associated with craniofacial formation. A follow-up study will focus on strategies to advance therapeutic approaches in HUWE1-linked pathologies. Project Number: 1R21DE036083-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Emilia Galperin (+1 co-PI) | Institution: UNIVERSITY OF KENTUCKY, LEXINGTON, KY | Award Amount: $444,438 | Activity Code: R21 | Study Section: Special Emphasis Panel[ZRG1 MGG-R (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11386971