Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Van Buchem disease decoded

17.06.2005


Study underscores the importance of non-coding DNA in disease determination



Today a team of scientists provides convincing evidence that the deletion of a large non-coding DNA segment on human chromosome 17 is responsible for Van Buchem disease. This genetic mutation is one of only a few disease-associated mutations discovered to date that alters a long-range transcriptional regulatory element. The study appears online in the journal Genome Research.

"Our study addresses a fundamental issue with regards to the majority of the human genome that is non-coding in nature, and its potential impact on human health," explains Dr. Gabriela Loots, a scientist in the Department of Genome Biology at Lawrence Livermore National Laboratory who headed the study. "Non-coding regions located far away from the genes they regulate are critical for normal gene expression and are capable of leading to dramatic abnormal phenotypes if altered or deleted."


Van Buchem disease is a rare hereditary disorder 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.

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.

Recently, however, a large 52-kilobase deletion was identified at a significant distance – approximately 35 kilobases – from the SOST gene in humans. This deletion, although associated perfectly with Van Buchem disease, removed a large non-protein-coding region; thus, its function, if any, in the development of the disease remained unclear.

The current study, which was led by Dr. Loots, was designed to rigorously investigate the underlying molecular mechanism by which this non-coding sequence might ultimately give rise to Van Buchem disease. Her team included researchers from Lawrence Berkeley National Laboratory (Berkeley, CA), the Novartis Institutes for BioMedical Research (Basel, Switzerland), and the DOE Joint Genome Institute (Walnut Creek, CA).

Dr. Loots and her colleagues engineered a human bacterial artificial chromosome (BAC) and generated transgenic mice with and without the 52 kilobases of DNA that are absent in Van Buchem patients. Although SOST was expressed normally in the early mouse embryo from both lines, SOST was dramatically downregulated in adult mice carrying the deletion, when compared to wild-type transgenic mice. These results provided strong evidence that the lack of SOST expression in humans homozygous for the 52-kilobase deletion is caused by a regulatory element – most likely an enhancer – that is located within the 52-kilobase region and that functions in a bone- and age-specific manner.

The team then utilized comparative sequence analyses and transient transfection assays to identify the actual enhancer sequence within the 52-kilobase deletion region that is responsible for SOST regulation. They aligned 140-kilobases of the human SOST region with the orthologous mouse sequence and identified seven evolutionarily conserved regions (ECRs). The seven ECRs were subjected to in vitro transient transfection enhancer analyses, and one of them – a 250-base-pair region named ECR5 – was found to drive expression in osteoblast-like cells.

These results provide a strong causal link between the 52-kilobase deletion and Van Buchem disease in humans. Drs. Michaela Kneissel and Hansjoerg Keller, collaborators on the project from the Novartis Institutes for BioMedical Research in Basel, Switzerland, point out that, in addition to addressing a fundamental problem in genomics, this project has clinical relevance. "Human genetic diseases of the skeleton, such as sclerosteosis and Van Buchem disease, provide a starting point for understanding the modulation of anabolic bone formation, and ultimately have the potential to identify key molecular components that can be used as new therapeutic agents to treat individuals suffering from bone loss disorders," say the researchers.

On an important scientific note, the methodological approaches employed by these researchers in elucidating the basis for Van Buchem disease will be widely applicable and very powerful in the characterization of other distant, cis-acting regulatory elements.

Maria A. Smit | EurekAlert!
Further information:
http://www.cshl.edu

More articles from Life Sciences:

nachricht Fine organic particles in the atmosphere are more often solid glass beads than liquid oil droplets
21.04.2017 | Max-Planck-Institut für Chemie

nachricht Study overturns seminal research about the developing nervous system
21.04.2017 | University of California - Los Angeles Health Sciences

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

Im Focus: Quantum-physical Model System

Computer-assisted methods aid Heidelberg physicists in reproducing experiment with ultracold atoms

Two researchers at Heidelberg University have developed a model system that enables a better understanding of the processes in a quantum-physical experiment...

Im Focus: Glacier bacteria’s contribution to carbon cycling

Glaciers might seem rather inhospitable environments. However, they are home to a diverse and vibrant microbial community. It’s becoming increasingly clear that they play a bigger role in the carbon cycle than previously thought.

A new study, now published in the journal Nature Geoscience, shows how microbial communities in melting glaciers contribute to the Earth’s carbon cycle, a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

New quantum liquid crystals may play role in future of computers

21.04.2017 | Physics and Astronomy

A promising target for kidney fibrosis

21.04.2017 | Health and Medicine

Light rays from a supernova bent by the curvature of space-time around a galaxy

21.04.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>