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Study finds genetic basis of rare bone disorder

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A US study has identified gene mutations that cause “dripping candle wax” bone disease.

Researchers at the National Institutes of Health (NIH) worked with 15 patients from around the world in a bid to learn more about the rare disorder, known as melorheostosis, which is characterised by excess bone formation that resembles dripping candle wax on x-rays.

The condition causes pain and bone deformity, which can limit the function of bones.

The findings of the study offer potential treatment targets for the disease, provide important clues about bone development, and may lead to insights about fracture healing and osteoporosis, according to NIH.

“Scientists previously assumed that the genetic mutations responsible for melorheostosis occurred in all cells of a person with the disorder,” said co-senior author Dr Timothy Bhattacharyya, head of the Clinical and Investigative Orthopaedics Surgery Unit at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at NIH. “Our team hypothesised that mutations might only occur in the affected bone tissue.”

Researchers compared samples of healthy and affected bone from each participant to look for differences in the exome, the portion of the genome that codes for proteins. By comparing genetic information from both samples in each patient, the team could pinpoint even low levels of the mutations.

The analysis revealed that eight of the 15 participants had mutations in the MAP2K1 gene in the affected bone only. MAP2K1 produces the protein MEK1 and has previously been linked to some types of cancerous growths as well as to conditions that lead to abnormal blood vessel formation in the head, face or neck.

In melorheostosis, all the identified MAP2K1 mutations affect a region of the MEK1 protein that normally suppresses its activity, and as a result they cause MEK1 to become overactive. The bone growth is considered benign and does not spread to other parts of the body.

“This is an exciting study of a very rare bone disorder that not only identified the responsible mutation in half of the patients, but uncovered fundamental information about the role of a cancer-related gene in the metabolic pathways of normal bone,” commented study co-senior author Dr Joan Marini, of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). “When we started, we had no preconceived causative pathways, but the participation of the patients has really changed the scientific landscape on this topic. Further studies on how this pathway works in both normal and mutant bone cells may have broad implications that could benefit a wider population.”

“Most adults have the problem of weakening bones as they grow older. These patients have the opposite problem as some of their bones are rock hard and still growing,” added Dr Bhattacharyya. “The prospect that we could somehow harness this pathway in the future is so exciting.”

The results of the study have been published in Nature Communications.