Table of Contents 21-4

Novel Deletions Downstream of SHOX Cause Léri-Weill Dyschondrosteosis

Léri-Weill dyschondrosteosis (LWD, MIM 127300) is a dominantly inherited bone dysplasia characterized by short stature, mesomelic limb shortening, and Madelung deformity of the forearm. Heterozygous deletions of the short stature homeobox-containing gene (SHOX) occur in LWD, and homozygosity for such deletions has been found in the more severe Langer mesomelic dysplasia (MIM 249700). SHOX resides in the pseudoautosomal region 1 (PAR1) of the short arm of the X and Y chromosomes. Its product is involved in cell cycle and growth regulation; and loss of SHOX function has also been implicated in Turner syndrome and in some cases of idiopathic short stature.

Detection of SHOX defects in only about 60% of LWD patients has raised the possibility that some of the remaining patients could have mutations in regulatory elements that lie upstream or downstream of the SHOX locus. Indeed, Benito-Sanz and colleagues have shown this to be the case.

The authors screened 80 LWD patients in whom mutation in the SHOX coding sequence had been excluded. Novel deletions in PAR1 downstream of SHOX were detected in 12 patients, 8 of whom came from families showing dominant inheritance of LWD. Deletion mapping revealed that the deletions were ~ 30–205 kb downstream of SHOX and varied in size from <81 to ~ 501 kb. Fine mapping disclosed a minimal commonly deleted region of 29 kb. The 5’ end of the deletion was similar in 5 families, suggesting the possibility of a hotspot for a deletion breakpoint.

Large-scale deletions were detected in 4 families, raising the possibility of a chromosomal rearrangement. However, inversion or translocation of the deleted region to an autosome was excluded by fluorescent in situ hybridization analysis, showing that the deletions were contiguous in all 4 cases.

Two explanations were considered. The first was the presence of a nearby second gene in PAR1 that influences skeletal growth much like SHOX. The authors found no evidence for a second gene. The second hypothesis, which was favored by the authors, was that a positive regulatory element for SHOX resides in the deleted region; deletion of this region would be expected to produce loss of SHOX expression. They noted other examples of long-distance gene regulators, especially involving transcription factors during development.

Benito-Sanz S, Thomas NS, Huber C, et al. A novel class of pseudoautosomal region 1 deletions downstream of SHOX is associated with Léri-Weill dyschondrosteosis. Am J Hum Genet. 2005;77:533–544.

Editor’s Comments: These results help to explain at least some of the 40% of patients in LWD in whom mutations in the SHOX coding sequence are not detected. They underscore a mechanism that is probably under-appreciated: disturbance of long-range gene regulation. It will be interesting to see how common this mechanism will be found to explain similar situations for other genetic diseases.

William A. Horton, MD