X-linked spondyloepiphyseal dysplasia tarda (SEDT, or SEDL) is a primary skeletal dysplasia affecting mostly spinal vertebral bodies and epiphyses. Previously, we have identified the SEDL gene and determined the spectrum of 21 different SEDL causing mutations. The SEDL gene is a highly conserved gene with an as yet unknown function. The yeast SEDL protein ortholog, Trs20p, has been isolated as a member of a large multi-protein complex ( approximately 10 proteins) called transport protein particle (TRAPP), which is involved in endoplasmic reticulum (ER)-to-Golgi transport. While the SEDL gene mutations cause a tissue-specific (epiphyses) and relatively mild phenotype, the Trs20p function is essential for the yeast cell. We now provide evidence that recombinant human SEDL protein is able to functionally complement the Saccharomyces cerevisiae TRS20 (TRAPP subunit 20 gene) knockout mutant. This finding strongly supports the speculated conserved nature of the SEDL/Trs20p function. To shed further light on the SEDL/Trs20p protein function, five different naturally occurring SEDL gene mutations have been tested in complementation studies. While two truncation mutations (157delAT and C271T) and one missense mutation (G139T) were unable to rescue the trs20Delta lethal phenotype, two other missense mutations (C218T and T389A) did complement trs20Delta. Interestingly, there is no obvious correlation between the nature and position of the SEDL mutation and the clinical severity of the disorder among the human SEDL patients. Although the identification of complementing SEDL gene mutations may suggest the existence of subtle phenotypic differences among SEDL patients, it might also point towards the identification of SEDL protein residues/domains specific for normal, vertebrate bone growth.

• PMID: 14597397
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Comparative Study | Journal Article | Research Support, Non-U.S. Gov't

Authors

Gécz J, Shaw MA, Bellon JR, de Barros Lopes M

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