( nes they regulate are critical for norm...)Researchers track down cause of a disfiguring bone disorder

To investigate the misregulation of the SOST gene, Loots and her colleagues genetically engineered a copy of the DNA segment containing the gene and used it to generate mice with and without the 52,000-base-pair region missing in Van Buchem patients. The deleted region is located about 35,000 base pairs "downstream" from SOST on human chromosome 17. While they found no difference in the activity of the SOST gene in early mouse embryos, the gene was dramatically "down-regulated," or less active, in adult mice carrying the deleted region than in the normal mice.

The findings are strong evidence that "the (Van Buchem) noncoding deletion removes a SOST-specific regulatory element," the team reported, indicating that the disease is caused by the absence of one or more distant enhancer elements in the deleted region that help direct the expression of the SOST gene in adult humans.

In an effort to locate the specific enhancer sequence responsible for SOST regulation, the team compared human and mouse DNA and found seven common segments within the 140,000-base-pair SOST region. Scientists assume that DNA segments that have been "conserved" from one organism to another during evolution play a biological role, or they would have been discarded as organisms evolved. By introducing the conserved segments into cells similar to osteoblasts (bone-forming cells), the team found that a 250-base-pair conserved region named ECR5 was able to drive SOST expression.

"This study represents a clear and unambiguous case in which altering noncoding genomic content has a deleterious impact on gene expression," the team reported, "demonstrating that mutations in distant regulatory elements are able to cause congenital abnormalities analogous to coding (gene) mutation
'"/>

Source:DOE/Lawrence Livermore National Laboratory