TRAPPC2 – X-linked Spondyloepiphyseal Dysplasia Tarda

The association between TRAPPC2 and X-linked spondyloepiphyseal dysplasia tarda is well‐established through extensive clinical, genetic, and functional evidence. Multiple independent case reports and multi‐patient studies have demonstrated segregation of various pathogenic mutations with the disease phenotype, including striking manifestations such as barrel‑shaped chest, disproportionate short stature, and early osteoarthritis. Notably, frameshift, nonsense, and splice‑site mutations have been identified across several unrelated families, with key reports documenting deletions and insertions that disrupt the normal TRAPPC2 gene product (PMID:12650905, PMID:14755465).

Genetic testing has revealed a consistent spectrum of deleterious variants. One representative mutation is c.387del (p.Val130fs), which was observed in an affected Jewish Ashkenazi family and aligns with findings from other studies that identified recurrent splice‑site alterations (e.g. c.93+5G>A) and deletion events, cumulatively supporting a loss‐of‐function mechanism. This genetic heterogeneity is further supported by multiple reports across diverse ethnic groups, underscoring the importance of robust variant interpretation in clinical diagnostics (PMID:11326333).

Segregation analysis within extended pedigrees has illustrated that affected males consistently inherit the mutant allele in an X‑linked recessive pattern. In several families, a significant number of affected relatives and obligate carriers further substantiate the gene–disease relationship, thereby reinforcing the utility of pedigree analysis for early and accurate diagnosis (PMID:10431248).

Functional studies provide compelling evidence for the pathogenicity of TRAPPC2 mutations. Complementation assays in yeast models demonstrated that wild‑type SEDL protein can rescue the lethal phenotype of a TRS20 knockout, whereas several mutant forms fail to function; these results corroborate the predicted loss‐of‐function mechanism observed in patient cells (PMID:14597397, PMID:19650763).

In addition, biochemical analyses have revealed marked protein misfolding and aberrant subcellular localization associated with these mutations. This mechanistic insight not only clarifies the cellular basis for the skeletal dysplasia but also suggests potential targets for therapeutic intervention in the future.

Collectively, the integration of genetic and experimental findings across multiple studies has yielded a definitive association between TRAPPC2 mutations and X‑linked spondyloepiphyseal dysplasia tarda. The consistent genetic evidence across diverse populations, combined with functional data confirming a loss‑of‑function mechanism, firmly establishes the clinical utility of TRAPPC2 testing in affected families.

Key Take‑home: Accurate molecular diagnosis of TRAPPC2 mutations enables precise carrier detection, informs genetic counseling, and facilitates early intervention strategies in X‑linked spondyloepiphyseal dysplasia tarda.

References

• Mutation Research • 2003 • A single nucleotide deletion of 293delT in SEDL gene causing spondyloepiphyseal dysplasia tarda in a four‑generation Chinese family PMID:12650905
• Nature Genetics • 1999 • Identification of the gene (SEDL) causing X‑linked spondyloepiphyseal dysplasia tarda PMID:10431248
• American Journal of Human Genetics • 2001 • A recurrent RNA‑splicing mutation in the SEDL gene causes X‑linked spondyloepiphyseal dysplasia tarda PMID:11326333
• Gene • 2003 • Human wild‑type SEDL protein functionally complements yeast Trs20p but some naturally occurring SEDL mutants do not PMID:14597397

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