The commonality of TSPEAR-related ARED14 sheds light on human origins
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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.
Adam Jackson, MBChB, MSc, MRCP
Adam Jackson is an academic clinical fellow in clinical genetics at the Manchester Centre for Genomic Medicine, UK. He obtained his medical degree from the University of Manchester in 2013 prior to starting clinical rotations in both adult and paediatric medicine in the North West of England before obtaining Membership of the Royal Colleges of Physicians (MRCP) in 2018. He obtained a Master’s degree in Genomic Medicine in 2017 and is currently completing his PhD studies on genomics of rare diseases. In March 2023, he was awarded the Robin-Winter prize from the UK Clinical genetics Society.
Siddharth Banka, MBBS, MRCPCH, PhD
Siddharth Banka is a Professor of Genomic Medicine and Rare Diseases at the University of Manchester, and a Consultant Clinical Geneticist at Saint Mary’s Hospital in Manchester. His research interest is in neurodevelopmental and congenital malformation disorders caused by defects in chromatin remodelling genes, copy number variations and inborn errors of metabolism. His group has led, or contributed to, the discoveries of ~50 novel genetic diseases. Using a combination of cellular and organismal models and benefiting from extensive internal, national and international collaborations his group has defined underlying mechanisms of several rare disorders. His research has a direct and immediate impact on health by improving diagnosis, management and treatments for patients, while simultaneously revealing fundamental biological insights. In his clinical practice I see children and adults with a range of genetic disorders. Overall, the aim of his work is to improve diagnosis, management, and treatments of patients with rare diseases.