Functional analysis of a novel nonsense variant c.91A>T of the gene in a Chinese family with X-linked recessive autosomal spondyloepiphyseal dysplasia tarda.

Spondyloepiphyseal dysplasia tarda (SEDT) is a condition involving late-onset, X-linked recessive skeletal dysplasia caused by mutations in the gene. In this paper, we identified a novel nonsense variant in a SEDT pedigree and analyzed the function of the variant in an attempt to explain the new pathogenesis of the TRAPPC2 protein in SEDT. Briefly, DNA and RNA samples from the peripheral blood of SEDT individuals were prepared. The causative variant in the Chinese SEDT family was identified by clinic whole-exome sequencing analysis. Then, we observed the mRNA expression of in patients and the mutant TRAPPC2 level and analyzed the protein stability and subcellular distribution by cell fluorescence and Western blotting. We also investigated the effect of knockdown on the expression and secretion of COL2A1 in SW1353 cells or primary human chondrocytes. Herein, we found a nonsense variant, c.91A>T, of the gene in the pedigree. mRNA expression levels were significantly decreased in the available peripheral blood cell samples of two affected patients. An study showed that the mutant plasmid exhibited significantly lower mRNA and protein of , and the mutant protein changed its membrane distribution. knockdown resulted in decreased expression and collagen II secretions. Our data indicate that the novel nonsense variant, c.91A>T, of the gene is the cause of SEDT in this pedigree. The variant results in a lowered expression of TRAPPC2 and then affects the expression and collagen II secretions, which may explain the mechanism of loss of function of the variant.