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Mutations resulting in a premature termination codon (PTC) are a major cause of inherited disorders, and the majority of these mutant RNA transcripts are subjected to nonsense-mediated mRNA decay (NMD). This RNA surveillance results in reduced mutant allele expression, the extent of which can impact on the clinical severity. The molecular mechanisms of NMD in mammalian cells, its relationship to splicing and translation, downstream sequence elements and binding factors remains only partially understood. Currently there is little information on whether the extent of NMD is gene- or tissue-specific, although nonsense mutation inhibition of RNA splicing has been shown to exhibit some tissue and gene specificity in vitro. Schmid metaphyseal chondrodysplasia results from heterozygous mutations in the gene for collagen X (COL10A1), expressed by the hypertrophic chondrocytes of growth plate cartilage. In one patient a PTC mutation has been shown to result in complete NMD and collagen X haploinsufficiency in cartilage. Here we show that, in this patient, and in another with a different collagen X PTC mutation also leading to complete NMD in cartilage, the mutant mRNAs were not subjected to NMD in non-cartilage cells (lymphoblasts and bone cells). These data suggest that novel RNA surveillance mechanisms may exist in cartilage and that tissue specificity of NMD could be of importance in understanding the molecular pathology of nonsense mutations. Furthermore, the demonstration of collagen X haploinsufficiency in the second patient to be studied at the level of tissue expression, confirms that nonsense mutations leading to complete mutant collagen X mRNA degradation in cartilage is an important molecular cause of SMCD.

Tissue-specific RNA surveillance? Nonsense-mediated mRNA decay causes collagen X haploinsufficiency in Schmid metaphyseal chondrodysplasia cartilage