TSPEAR and ectodermal dysplasia syndrome

TSPEAR, a gene encoding a protein with thrombospondin-type laminin G domains and EAR repeats, has been strongly implicated in ectodermal dysplasia syndrome. Multiple studies have observed biallelic loss‑of‑function variants in TSPEAR among affected individuals, with patients presenting characteristic features including sparse scalp hair and tooth agenesis (PMID:34042254).

Genetic evidence from a novel cohort study identified 13 probands with biallelic TSPEAR variants, including the loss‑of‑function variant c.1766G>A (p.Trp589Ter), supporting an autosomal recessive inheritance pattern. In these cases, segregation analysis further demonstrated that additional affected relatives carried the same variants across independent families (PMID:34042254; PMID:37525042).

The variant spectrum in TSPEAR is diverse, spanning frameshift, nonsense, and splice‐site mutations. Notably, several truncating variants recur in different populations, suggesting potential founder effects and reinforcing the gene’s pathogenic role in ectodermal dysplasia syndrome (PMID:37525042).

Functional assessment studies have demonstrated that TSPEAR disruption leads to impaired Notch signaling, a pathway critical to ectodermal organogenesis. Experimental models, including tspear knockout zebrafish and mouse hair follicle organ cultures, replicate key phenotypic elements such as hypodontia and scalp hypotrichosis, thereby bridging molecular genetic findings with clinical manifestations (PMID:37009414).

Additional functional evidence from in vitro assays shows that TSPEAR deficiency results in reduced NOTCH1 protein levels and increased apoptosis in epithelial cells, further clarifying its mechanistic role in normal tooth and hair development (PMID:27736875).

Although TSPEAR was previously considered in the context of nonsyndromic hearing loss, comprehensive phenotypic analyses indicate that its primary association is with ectodermal dysplasia rather than isolated auditory impairment. This distinction simplifies diagnostic considerations by excluding competing genetic causes for hearing loss when TSPEAR variants are identified.

In summary, the convergence of robust genetic data and corroborative functional studies underscores a strong association between TSPEAR variants and ectodermal dysplasia syndrome. This evidence supports the adoption of TSPEAR in diagnostic workflows and paves the way for refined therapeutic strategies in clinical practice.

References

• American journal of medical genetics. Part A • 2021 • TSPEAR variants are primarily associated with ectodermal dysplasia and tooth agenesis PMID:34042254
• Advances in experimental medicine and biology • 2023 • Clinical and Molecular Genetic Analysis of Cases with Ectodermal Dysplasia PMID:37525042
• HGG advances • 2023 • Clinical, genetic, epidemiologic, evolutionary, and functional delineation of TSPEAR‑related autosomal recessive ectodermal dysplasia 14 PMID:37009414
• PLoS genetics • 2016 • Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis PMID:27736875

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