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.
