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Discovery About Rare Bone Disease May Also Hold Clues About Bone Health

Allison Inserro
National Institutes of Health researchers have uncovered a genetic basis of a rare bone disease known as melorheostosis and said the discovery could offer potential treatment targets, provide clues about bone development, and lead to insights about fracture healing and osteoporosis.
National Institutes of Health (NIH) researchers have uncovered a genetic basis of a rare bone disease known as melorheostosis and said the discovery could offer potential treatment targets, provide clues about bone development, and lead to insights about fracture healing and osteoporosis.

The disease causes 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. There are about 400 known cases of this rare disease worldwide. The discovery was published in Nature Communications.

Fifteen unrelated adults with the condition underwent biopsies of both affected and unaffected bones at the NIH Clinical Center. 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. 

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

Comparing genetic information from both samples in each patient allowed the team to pinpoint even low levels of the mutations.  The analysis revealed that 8 of the 15 participants had mutations in the MAP2K1 gene in the affected bone only. MAP2K1 produces the protein MEK1. The gene MAP2K1 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, causing MEK1 to become overactive. The bone growth is considered benign and does not spread to other parts of the body.

“When we started, we had no preconceived causative pathways, but the participation of the patients has really changed the scientific landscape on this topic,” said study co-senior author Joan Marini, PhD, MD, in a statement.  “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,” said Bhattacharyya. “The prospect that we could somehow harness this pathway in the future is so exciting.” 

The disease occurs in males and females equally, without familial clustering, and often affects multiple contiguous bones unilaterally in an asymmetric distribution. Symptoms of may begin in childhood and the diagnosis is usually made by the age of 20. Patients are diagnosed by a combination of clinical findings, radiographs and bone scans. There is no definitive diagnostic test or specific treatment for the condition.

The study was supported by the NIH and the Melorheostosis Association. The Ludwig Boltzmann Institute of Osteology in Austria worked with the NIH on this study.


Kang H, Jha S, Deng Z, et al.  Somatic activating mutations in MAP2K1cause melorheostosis. Nat Commun. 2018;(9):1390.

[published online April 11, 2018].

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