IADR Abstract Archives
Characterization of the Craniosynostosis Phenotype in Loeys-Dietz Syndrome Type 2
Objectives: Loeys-Dietz Syndrome (LDS) is a rare autosomal dominant connective tissue disorder caused by mutations along TGF-β signaling pathway with six subtypes (LDS1-6). Patients with LDS exhibit various degrees of craniosynostosis with unclear pathophysiology. Our study identified that LDS2 (mutations in TGFBR2) is associated with the most severe phenotypic presentation (severity scoring based on loss of patency and sinuosity using CBCTs), with lambdoidal suture being the most affected. It was intriguing because lambdoidal craniosynostosis is generally rare in syndromic craniosynostosis. Our objectives were to determine if a mouse model of LDS2 (Tgfbr2G357W/+ mice) recapitulates the human findings and to assess the molecular mechanism associated with the phenotype.
Methods: Craniosynostosis severity in LDS2 mouse was scored based on the laterality and presence of microfusions/frank craniosynostosis among the three sutures using uCT/3D imaging at four developmental stages (2, 6, 12 and 24 weeks). Molecular changes were assessed using bulk RNASeq analysis on one week old LDS2 mice vs WT littermates using posterior lambdoidal (PL) suture and anterior lambdoidal (AL) suture.
Results: LDS2 mouse model recapitulated the phenotype of human LDS2 uniquely affecting the PL suture as early as two weeks while other sutures remain unaffected until six weeks. The severity of the phenotype increased from microfusions to frank craniosynostosis over time. RNASeq analysis revealed four annotated genes that were differentially expressed in AL suture while PL suture showed 849 affected genes. Pathway analysis revealed canonical pathways and upstream regulators associated with the biological process of muscle contraction at the top of the gene list. Six1, Pax7 and Myod1 were top predicted molecules in the causal network that are associated with both craniofacial and muscle development.
Conclusions: Lambdoidal craniosynostosis is a characteristic phenotype of both human and mouse LDS2 with possible association of novel genes and pathways involved in muscle development.
Methods: Craniosynostosis severity in LDS2 mouse was scored based on the laterality and presence of microfusions/frank craniosynostosis among the three sutures using uCT/3D imaging at four developmental stages (2, 6, 12 and 24 weeks). Molecular changes were assessed using bulk RNASeq analysis on one week old LDS2 mice vs WT littermates using posterior lambdoidal (PL) suture and anterior lambdoidal (AL) suture.
Results: LDS2 mouse model recapitulated the phenotype of human LDS2 uniquely affecting the PL suture as early as two weeks while other sutures remain unaffected until six weeks. The severity of the phenotype increased from microfusions to frank craniosynostosis over time. RNASeq analysis revealed four annotated genes that were differentially expressed in AL suture while PL suture showed 849 affected genes. Pathway analysis revealed canonical pathways and upstream regulators associated with the biological process of muscle contraction at the top of the gene list. Six1, Pax7 and Myod1 were top predicted molecules in the causal network that are associated with both craniofacial and muscle development.
Conclusions: Lambdoidal craniosynostosis is a characteristic phenotype of both human and mouse LDS2 with possible association of novel genes and pathways involved in muscle development.