Discovery of New Skeletal Disorder May Shed Light on Another

A new paper details the case of a family with 2 children with a rare skeletal disorder similar to Jansen metaphyseal chondrodysplasia, and how investigators in Los Angeles and the Czech Republic discovered the genetic cause of the condition.

Jansen metaphyseal chondrodysplasia (JMC) is an extremely rare progressive disorder causing portions of the arm and leg bones to develop abnormally. Telltale signs of the condition include unusual cartilage formations and subsequent abnormal bone formation of the long bones resulting in short arms and legs and short stature, or short-limbed dwarfism, which becomes apparent during childhood. JMC can also affect the cartilage development and bone formation in the hands and feet and may lead to loss of muscle mass and gradual swelling of certain joints, especially the hips and knees. There are currently about 30 genetically-confirmed cases of JMC worldwide, with 6 in the United States.

The disorder is caused by a gene mutation in the PTH/PTHrP receptor, which leads to constitutive activation of the receptor independent of PTH or PTHrP. Parathyroid hormone helps to regulate the levels of calcium in the blood. Along with x-ray, patients with JMC can receive a diagnosis through blood and urine analysis, which reveal abnormally high levels of calcium in confirmed cases.

In a new study published in the journal Science Translational Medicine, investigators from the University of California—Los Angeles and Masaryk University in Czech Republic detail their findings of a previously uncharacterized recessively inherited skeletal disorder in a pair of siblings which, while sharing radiographic similarities to JMC, also had unique features that did not match any of the currently classified skeletal disorders.

Using genome analysis, the investigators discovered that this new disorder is caused by a gene called SIK3 which when mutated causes a very complex skeletal disorder and, in some cases, an abnormal immune system. Based on the abnormalities the study authors observed, they were able to determine that the SIK3 gene is involved in regulating the mTOR pathway. This pathway is a master growth regulator, sensing and integrating diverse cues that include those that come from growth factors, energy levels, cellular stress, and amino acids. Because of the radiographic overlap with JMC, the investigators found that the gene involved in that disorder also interacts with SIK3, leading to a final common mechanism.

In an interview with Rare Disease Report^®, first author Deborah Krakow, MD, explained that the condition is unique despite radiographic similarities to JMC.

“The condition does not yet have a name, but at least for now SEMD -SIK3 type. It is distinct from JMC by the type of inheritance, it is recessive and JMC is dominant. It is also associated with similar but distinct radiographic findings; it has a severe immune deficiency and development delay,” Dr. Krakow said, adding that the discovery offers new insight into the development of treatment for JMC. “We are working toward using SIK3 as a way to modulate the mTOR pathway and increase its activity as a way to treat the abnormal PTH/PTHrP receptor.”

For the next stage of their research, the study authors say they will be working to understand how SIK3 regulates mTOR and how the DEPTOR molecule regulates skeletal cells.

The study was conducted over 3 years with funding from the National Institutes of Health.