The commonality of TSPEAR-related ARED14 sheds light on human origins

Description

Dr. Adam Jackson, MBChB, MSc, MRCP, will discuss autosomal recessive ectodermal dysplasia type 14 caused by biallelic variants in TSPEAR. He will discuss a newly described cohort of individuals with ARED14 and outline the main presenting features whilst also exploring the evolutionary origins of several TSPEAR founder variants which may explain their high frequency in present day Europeans. 

Overview of Presentation

• Autosomal ectodermal dysplasia type 14 is caused by biallelic deleterious variants in TSPEAR, which encodes a protein of unknown function. 
• Hypodontia and conical-shaped teeth are the predominant features of ARED14 
• Missense variants perturb the beta propeller formed by several EAR domains in TSPEAR 
• Multiple founder variants in TSPEAR, originating at the end of the Last Glacial Maximum, are responsible for ARED14 in non-Finnish Europeans with up to 1 in 140 of these individuals being carriers for ARED14. 
• TSPEAR shows restricted expression to ectodermal placodes in keeping with its Drosophila ortholog, Closca, which is well known to coordinate extracellular matrix (ECM)-dependent signalling. 
• Knockout of TSPEAR orthologs in zebrafish recapitulates the human dental phenotype whilst also demonstrating a possible role for TSPEAR in WNT signalling in fin regeneration 
• TSPEAR’s macromolecular structure makes it a likely candidate for WNT ligand sequestration in the ECM.