Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR-related autosomal recessive ectodermal dysplasia 14

Research output: Contribution to journalResearch articleContributedpeer-review


  • University of Manchester
  • Manchester University NHS Foundation Trust
  • Oklahoma Medical Research Foundation
  • Birmingham Women's and Children's NHS Foundation Trust
  • Cambridge University Hospitals NHS Foundation Trust
  • Guy's and St Thomas' NHS Foundation Trust
  • Great Ormond Street Hospital for Children NHS Trust
  • Oxford University Hospitals NHS Foundation Trust
  • University Hospitals Bristol and Weston NHS Foundation Trust
  • Belfast Health and Social Care Trust


TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A-related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the β-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca, an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara−/−;tspearb−/− double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants.


Original languageEnglish
Article number100186
Pages (from-to)1-19
Number of pages19
JournalHuman genetics and genomics advances : HGG advances
Issue number2
Publication statusPublished - 13 Apr 2023

External IDs

PubMed 37009414


ASJC Scopus subject areas


  • Autosomal recessive ectodermal dysplasia type 14, Closca, Conical teeth, Ectodermal dysplasia, Enamel knot, Extracellular matrix dependant signalling, Hypodontia, TSPEAR, WNT10A, zebrafish fin regeneration, Tooth/pathology, Zebrafish, Phylogeny, Animals, Ectodermal Dysplasia/epidemiology, Mice

Library keywords