+-------------------+--------------------------------------------------+
| Genome Research,  |                                                  |
| 2005, 15:928-935  |                                                  |
|                   |                                                  |
| Genomic deletion  |                                                  |
| of a long-range   |                                                  |
| bone enhancer     |                                                  |
| misregulates      |                                                  |
| sclerostin in Van |                                                  |
| Buchem disease    |                                                  |
|                   |                                                  |
| Loots G. G.       |                                                  |
+-------------------+--------------------------------------------------+
| Van Buchem        | Van Buchem disease is a rare hereditary disorder |
| disease           | of the skeletal system that is characterized by  |
|                   | progressive osteosclerosis, particularly in the  |
|                   | skull and mandible, but also in the clavicles,   |
|                   | ribs, and diaphyses of long bones. Consequences  |
|                   | of this increased bone mass usually include      |
|                   | facial distortions and pinching of cranial       |
|                   | nerves, and the increased nerve pressure often   |
|                   | leads to deafness and blindness. Onset of the    |
|                   | disease generally occurs during childhood and is |
|                   | manifested only in individuals carrying two      |
|                   | copies of the mutant allele. VB patients never   |
|                   | display syndactyly of the digits.                |
+-------------------+--------------------------------------------------+
| sclerostin (SOST) | The locus responsible for Van Buchem disease was |
|                   | previously mapped to the short arm of human      |
|                   | chromosome 17 near the gene sclerostin (or       |
|                   | SOST), whose protein product functions as a      |
|                   | negative regulator of bone formation. Mutations  |
|                   | in the protein-coding regions of SOST are known  |
|                   | to be responsible for sclerosteosis, another     |
|                   | genetic disorder with attributes similar to Van  |
|                   | Buchem disease. Because SOST was therefore a     |
|                   | strong causal candidate for Van Buchem disease,  |
|                   | scientists screened the SOST coding sequence for |
|                   | associated mutations, but to no avail.           |
|                   |                                                  |
|                   | SOST, a novel bone morphogenetic protein (BMP)   |
|                   | antagonist and negative regulator of bone        |
|                   | formation, is expressed in osteogenic cells.     |
+-------------------+--------------------------------------------------+
| BAC               | bacterial artificial chromosomes (BAC or PAC)    |
|                   | vectors                                          |
+-------------------+--------------------------------------------------+
| assay             | Qualitative or quantitative determination of the |
|                   | components of a drug (or material such as ore).  |
+-------------------+--------------------------------------------------+
| In vitro          | In the test tube.                                |
+-------------------+--------------------------------------------------+
| In vivo           | In the living (tissue, body, organism)           |
+-------------------+--------------------------------------------------+
| BMP               | bone morphogenetic protein (BMP)                 |
+-------------------+--------------------------------------------------+
| In situ           | In the place (exactly where the phenomenon       |
|                   | occurs)                                          |
+-------------------+--------------------------------------------------+
| Allelic/allele    | One member of a pair or series of genes that     |
|                   | occupy a specific position on a specific         |
|                   | chromosome.                                      |
+-------------------+--------------------------------------------------+
| Sclerosteosis     | More severe and occasionally displays syndactyly |
|                   | of the digits.                                   |
+-------------------+--------------------------------------------------+
| syndactyly        | The condition of having two or more fused        |
|                   | digits, as occurs normally in certain mammals    |
|                   | and birds.                                       |
+-------------------+--------------------------------------------------+

**Thesis**

Scientists have tracked down the biological trigger that gives rise to
Van Buchem disease, a hereditary bone disorder characterized by
progressively increasing bone density, particularly in the skull and
lower jaw. Consequences of increased bone density in Van Buchem patients
include facial distortions and pinching cranial nerves, which can lead
to blindness and deafness. The findings from this study provide insight
into long-range gene regulation, and could lead to new treatments for
bone-loss disorders, such as osteoporosis, and other crippling bone
disorders.

In 2005, a research team from Lawrence Livermore and Lawrence Berkeley
national laboratories, the Novartis Institutes to BioMedical Research in
Switzerland, and the DOE Joint Genome Institute in Walnut Creek,
California, led by Gabriela Loots, of Livermore's Genome Biology
Division, characterized the human mutation associated with the
malfunctioning of the SOST gene. The SOST gene is a bone morphogentic
protein (BMP) that plays an important role in regulating bone formation.
The team of scientists determined how SOST plays a key role in
triggering Van Buchem disease.

"Our study addresses a fundamental issue with regard to the majority of
the human genome that is noncoding in nature, and its potential impact
on human health," Loots siad, "Noncoding regions located far way from
the genes they regulate are critical for normal gene expression and are
capable of leading to dramatic abnormal phenotypes if altered or
deleted."

The study is one of the first to show that an absence of a noncoding
region effectively alters a regulatory element of a gene. In the past,
vast regions of DNA that do not contain instructions for making
proteins, known as noncoding regions, were thought to have no biological
function. Recent evidence such as this suggests, however, that noncoding
regions play an important role in switching distant genes on and off.

The team demonstrated that by deleting a 52-kb noncoding region of DNA
some distance from the SOST gene, the SOST-related regulatory element
was effectively turned off. In vitro and in vivo experiements on mice
showed that without this regulator, bone production went up without
constraint, causing excessive bone density.

The team present their findings in an article entitled "Genomic deletion
of a long-range bone enhancer misrgulates scleostin in Van Buchem
disease," published by *Genome Research*, June 17, 2005. You can read
the complete article, in PDF format, by clicking here.