TAPT1 and Osteogenesis Imperfecta

TAPT1 has emerged as a critical gene in the etiology of osteogenesis imperfecta, a hereditary skeletal disorder primarily affecting collagen type I synthesis and extracellular matrix regulation (PMID:37292039). The evidence comprises both individual case reports and multi‐patient studies that collectively support an autosomal recessive mode of inheritance.

In a multi‐patient study, six affected individuals were shown to carry a deep intronic variant, c.1237-52G>A, that segregated with the osteogenesis imperfecta phenotype (PMID:36652330). This variant, identified by RNA-seq and homozygosity mapping, is predicted to perturb pre-mRNA splicing and result in aberrant transcript processing, thereby creating a protein-null allele.

Segregation analysis in these families, although not quantified in terms of additional affected relatives, reinforces a recessive inheritance pattern and affirms the genetic transmission of the defect. The consistency of the variant’s occurrence in unrelated probands strengthens the association between TAPT1 and the osteogenesis imperfecta phenotype.

Genetic evidence is further bolstered by the identification of TAPT1 mutations in a separate case report where extracellular matrix alterations were linked to signaling disruptions central to the disease pathology (PMID:37292039). The concordance between the molecular findings across studies underscores a shared mechanism of loss-of-function.

Functional studies have demonstrated that the identified deep intronic mutation leads to skipping of exon 12, a change that is predicted to abolish normal protein function. This disruption of TAPT1 perturbs extracellular matrix dynamics and collagen biosynthesis, both of which are integral to bone strength and integrity in osteogenesis imperfecta (PMID:36652330).

Integrating the collected genetic and functional data, there is a compelling narrative linking dysfunctional TAPT1 to the pathogenesis of osteogenesis imperfecta. The evidence, derived from independent studies with robust genetic and mechanistic support, converges on a loss-of-function model that directly impacts bone structural integrity.

While further studies may expand upon these findings, the current evidence reaches a level that is highly supportive for diagnostic application, commercial testing, and future research publications. Clinicians and researchers should consider TAPT1 mutation screening as a valuable tool in the evaluation of osteogenesis imperfecta cases.

Key Take‑home: Mutations in TAPT1, particularly the deep intronic variant c.1237-52G>A, represent a strong molecular basis for osteogenesis imperfecta, underscoring the gene’s clinical utility in diagnostic and therapeutic contexts.

References

• EMBO molecular medicine • 2023 • TAPT1-at the crossroads of extracellular matrix and signaling in Osteogenesis imperfecta PMID:37292039
• EMBO molecular medicine • 2023 • A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI-NET sequencing PMID:36652330

Evidence Based Scoring (AI generated)