Research & Development Researchers discover possible therapy for rare limb disorder

Researchers discover possible therapy for rare limb disorder


Researchers from Columbus, Ohio’s Nationwide Children’s Hospital may have discovered a therapy to address certain components of the Robinow syndrome before limb length of infants is affected. 

Disorders associated with Robinow syndrome are extremely rare, yet they can have significant effects. Infants born with the genetic disorder frequently have a cleft palate and grow short limbs in addition to the lifetime chance of kidney and heart abnormalities. 

There is no medical cure other than surgery.

Researchers explained how they treated pregnant mice with a medication that restores damaged cell signalling pathways, which allowed them to normalise the limb length of mouse pups with Robinow syndrome. They think that humans may benefit from their discoveries as well.

Rolf Stottmann stated in a press release:

“The idea of treating the limb bones medically rather than surgically is a really important proof of principle, which we demonstrate in this study. We are very excited to test if this could work in the context of other genes associated with autosomal dominant Robinow Syndrome.”

The focus gene, called FRIZZLED2 or FZD2, is essential for development prior to birth. It is an essential component of the Wnt signalling pathways and encodes a protein that regulates cell connections throughout the growth of organs and tissues. Via receptors on the cell surface, they communicate with cells. Some of the signals are lost and growth is interfered with if the FZD2 protein is changed.

When Stottmann’s team discovered that a mother and daughter with the disorder both possessed a mutant variant of the gene that didn’t occur in unaffected family members, they were the first to connect FZD2 to Robinow syndrome. Results showed that FZD2 was responsible for the autosomal dominant form of Robinow syndrome, which arises when only one copy of a defective gene is present. In the latest study, researchers replicated the mutation in a mouse model using CRISPR/Cas9 genome-editing technology, causing mice pups born to moms with the mutation to have the same facial and limb traits as human children with Robinow syndrome.

The researchers were aware from several previous types of research that the medication IIIC3a, which promotes some Wnt signalling pathways, might prevent the development of cleft palates in mouse pups with a different genetic defect. They administered IIIC3a daily to a group of pregnant mice with Robinow syndrome starting around halfway through their gestation period to test if it would also function in this situation.

 While the length of their limbs was normal, the pups of the treated mice still had cleft palates.

Several questions were raised regarding why the medicine might lengthen limbs but not correct a cleft palate. The researchers hypothesised that IIIC3a was operating on canonical signalling pathways, which, when addressed, restored normal length to the pups’ long bones. It is possible that the cleft palate was caused by non-canonical signalling pathways, and poorly understood mechanisms, and that the medicine had no effect on those processes because of the FZD2 mutation.

However, the researchers pointed out that a cleft palate is easier to repair than bone length. The study suggested that medical intervention would be an alternative for therapeutic treatment, especially when the genetic diagnosis might possibly be obtained years before long bone growth is finished in human development.

The goal of the researchers’ upcoming research will be to comprehend the effects of the FZD2 mutations on Wnt signalling. They want to apply this strategy to additional gene variants linked to autosomal dominant Robinow syndrome as well.

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