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 five 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.

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.

Judith G. Hall, OC, MD

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