The Sh3Pxd2bnee-/- mouse: an attractive model unveiling developmental features in Frank-ter-Haar Syndrome

Frank-ter Haar syndrome (FTHS) is an inherited disease associated with variants of the SH3PXD2B gene, encoding for the podosomal adaptor protein known as TKS4. FTHS is characterized by multiple skeletal abnormalities, developmental delay and severe craniofacial dysmorphology. This study provides an in-depth characterization of the calvarial phenotype of a mouse model of FTHS and investigates the potential underlying molecular and transcriptomic mechanisms. The Sh3Pxd2bnee-/- mouse presents with craniofacial malformations, AQ4 disrupted suture patterning, decreased osteoregeneration, cell proliferation and migration both in vitro and in vivo, and impaired podosome formation. Transcriptomic analysis revealed downregulation of genes involved in ribosome biogenesis. Moreover, ribosomal RNA accumulates in cell protrusions of migrating cells. We established that the craniofacial phenotype of the Sh3Pxd2bnee-/- mouse is governed by impaired cell migration and proliferation due to dysfunctional podosome formation, particularly in neural crest-derived tissues. Transcriptomic and molecular data suggest altered ribosome-related processes, although further investigation is needed to clarify the underlying mechanisms. Overall design: RNA-seq profiling of RNA extracted from skulls of WT and Sh3Pxd2bnee-/- mice at postnatal day 15