Researchers at the Karolinska Institute have discovered a new and rare skeletal disease. In a newly published study, they describe the molecular mechanism of the disease, in which small RNA molecules play a role that has never before been observed in a congenital human disease.1 The results are important for affected patients, but can also help scientists to understand other rare diagnoses.

The newly identified skeletal disease was first observed in a parent and a child from a Swedish family.

Giedre Grigelioniene, MD, PhD

Giedre Grigelioniene, MD, PhD, Karolinska Institute.

“They came to my clinic,” explains the study’s lead author, Giedre Grigelioniene, MD, PhD, an associate professor of molecular medicine and surgery at the Karolinska Institute. “They’d received a different diagnosis previously, but it didn’t fit with what we were seeing in the x-rays. I was convinced that we were looking at a new diagnosis that had not been described before.”

Grigelioniene and her colleagues describe the new skeletal disease as a type of skeletal dysplasia. Together with Fulya Taylan, PhD, assistant professor of molecular medicine and surgery at the Karolinska Institute, the researchers identified the disease-causing mutation in a gene called MIR140. The gene does not give rise to a protein but to a micro-RNA (miR-140), a small RNA molecule that regulates other genes.

Working with Tatsuya Kobayashi, MD, PhD, an associate professor of medicine at Massachusetts General Hospital, the researchers produced a mouse model of the disease, using the CRISPR-Cas9 ‘molecular scissors’ technique to create a strain carrying the identified mutation. They subsequently observed that the animals’ skeletons displayed the same aberrations as the three patients in the study.

The researchers also showed that the identified mutation leads to the abnormal expression of several important genes in the cartilaginous growth plates and the ends of the long tubular bones. Some genes that are normally suppressed by miR-140 are expressed, while others are down-regulated.

“This causes a change in skeletal growth, deformed joints, and the delayed maturation of cartilage cells in the patients, who have short stature, small hands and feet, and joint pain,” notes Grigelioniene.

The identified mutation knocks out a normal function of the micro-RNA, and replaces it with a different function. The mechanism is called ‘neomorphic mutation,’ and it has never before been described as involving small RNAs in human congenital disease.

According to Grigelioniene, the results are important for both patients with the disease and scientists interested in how small regulatory RNA molecules are involved in the development of human congenital disease.

“We plan to examine whether similar mechanisms with mutations in small RNA genes are involved in the development of other rare congenital disorders,” she says. “As for patients who already have this disease, the results mean that they can choose to use prenatal fetal diagnostic, in order not to pass the disease on to their children.”


  1. Grigelioniene G, Suzuki HI, Taylan F, et al. Gain-of-function mutation of microRNA-140 in human skeletal dysplasia. Nat Med. Epub ahead of print, February 25, 2019; doi: 10.1038/s41591-019-0353-2.