Friday, May 9, 2025
5/9/2025
Mechanisms of Macroglossia in Beckwith-Wiedemann Syndrome - PROJECT SUMMARY/ABSTRACT Macroglossia (severe tongue overgrowth) leads to catastrophic morbidity and mortality in infants with Beckwith-Wiedemann Syndrome (BWS). Respiratory distress and airway obstruction are often present at birth, and the only current treatment is surgical resection of the tongue. Surgery can have significant side effects, including risk for lingual nerve injury and infection and is not always curative. Tongue muscle is considered to be similar to skeletal muscle, but in-depth analysis is currently limited in both human and mouse models. Several other skeletal muscle diseases have been linked to defective signaling in satellite cells and the interaction between specific muscle cell types. The specific signaling pathways causing macroglossia have not been defined. There are two critical genes altered in BWS that may play a role in tongue overgrowth (Cyclin dependent kinase 1C (CDKN1C) and/or Insulin-like growth factor 2 (IGF2)). Clinical observation of hundreds of patients with BWS suggests that the macroglossia phenotype can be divided based on the increased state of IGF2 versus decreased state of CDKN1C in each patient. This work will focus on how the genetic changes seen in BWS lead to distinct BWS tongue phenotypes based on the cell composition, expression, and function of these BWS genetic subtypes. We have the largest collection of BWS tongue samples in the United States, including tongue samples with alterations in each of these genes, which will allow us to study the contribution of each gene to macroglossia. Through our collaborative research team, we have assembled the expertise to define the cell types, cellular drivers and the pathways causing macroglossia. Our approach includes single-nuclei transcriptomic analysis of cell composition and interaction and in situ analysis of the interface between the key cell types through immunohistochemistry. We will separate these cell types in the tongue through sorting and characterize satellite cell proliferation and differentiation potentials based on their genetic alterations (IGF2HIGH, CDKN1CLOW, IGF2HIGH+CDKN1CLOW). Finally, we will define the in vivo role of the satellite cells from the different BWS subtypes (IGF2HIGH, CDKN1CLOW, IGF2HIGH+CDKN1CLOW) in a xenograft tongue model. This proposal will define the cell composition and cell-specific contributions to tongue overgrowth at the individual and the organ level. This work represents a critical step towards developing targeted non-surgical therapeutics for infants with BWS and macroglossia along with related muscle diseases.
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