PTBP3 Associated With 9q32 Locus Is a Candidate Gene for Nager Syndrome

Background: Mandibulofacial dysostosis (MFD) is a congenital disorder characterized by defects in facial bones of neural crest origin. Nager syndrome combines many features of MFD with limb defects. Mutations in SF3B4, a gene located on chromosome 1 that encodes a protein of the spliceosome, were identified as a cause for Nager syndrome in approximately 60% of patients. Methods: A region of chromosome 9 (9q32) that contains 35 genes has also been linked to Nager syndrome and may account for some affected individuals for which the causes of the disease have not been identified. Because Nager syndrome belongs to a rapidly growing list of craniofacial syndromes caused by pathogenic variants of splicing factors, we focused our attention on two genes in the 9q32 region that encode factors involved in pre-mRNA processing, PRPF4 and PTBP3, and analyzed their role in craniofacial development in Xenopus embryos. Results: Loss-of-function experiments in Xenopus laevis embryos indicate that Ptbp3 is required while Prpf4 is dispensable for neural crest gene expression at the neurula stage, a phenotype that is partially rescued by expression of human PTBP3. At the tadpole stage, Ptbp3-depleted embryos have severely hypoplastic craniofacial cartilages, phenocopying the defects observed in Sf3b4 morphant tadpoles. Furthermore, ptbp3 expression is significantly increased in Xenopus tropicalis sf3b4 Null embryos as compared to wild-type siblings. Conclusion: We propose that dysregulation of PTBP3 expression may cause Nager syndrome in a subset of patients who do not have a mutation in SF3B4.