The gene for X-linked form of spondyloepiphyseal dysplasia tarda has been identified as SEDT, a protein that apparently plays a role in endoplasmic reticulum-to-Golgi transport and involves subcellular localization of normal sedlin constructs. The protein is relatively small with 140 amino acids. It is located in the non-X-inactivated part of Xp22. This suggests that female carriers express sufficient normal gene to avoid the disease.
The present study looked at 36 unrelated cases and attempted to make phenotype/genotype correlations. Mutations could be found in 30 individuals. The 6 individuals in which mutations were not found either lacked a strong family history or convincing physical features, and therefore, may represent other diseases. Twenty-one different gene mutations were observed among the 30 cases, and in those cases with several identical mutations, hypeotype analysis suggests that they arose separately and, therefore, do not represent a founder effect.
Intrafamilial variation was certainly observed; however, mutations occurring toward the five1 end of the SEDL gene (mutations in Exons 3 and 4) resulted in kyphosis and scoliosis with severe pain early in life and with more debilitating types of complications. This was observed while mutations in Exons 5 and 6 resulted in milder clinical features.
Mutations were spread throughout the gene, including point mutations, splice alterations, insertions, deletions, and complex rearrangements. The most common type of mutation was a deletion. There was a 10 fold greater occurrence of deletions than would be expected. This may represent slippage during homologous recombination between the Y and X chromosome.
The SEDL phenotype may be explained by reduction in endochondral bone formation in the epiphysis, particularly in the vertebral bodies. A timely switch to up regulate the endogenous expression of a pseudo gene on chromosome 19 might provide gene therapy. The authors are undertaking a study of SEDL mutations in premature osteoarthritis.
Gedeon, AK, et al. Am J Hum Genet. 2001;68:1386-1397.
Editor’s Comment: When genes are identified for the chondrodysplasias, the possibility of making phenotype/genotype correlations and understanding the basic molecular biology are very enticing. This paper is a lovely demonstration of how a great deal can be learned in rare disorders by large international collaborations. This work hopefully will lead both to a better understanding of disease and to potential therapies.