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Researchers Uncover Cause of Rare Bone Disorder

August 23, 2021

Researchers at the Swiss research university Ecole Polytechnique Federale de Lausanne have identified a gene that if expressed too early during embryonic development, can cause a rare disorder of bone growth.

Photo: Christopher Chase Bolt, a postdoc in Duboule’s lab and led author of the Nature Communications study

Mesomelic dysplasias are a group of rare genetic conditions characterized by extreme shortening of the long bones in the arms and legs. It has not been understood, though, what causes the condition.

Now, the EPFL researchers report in the Journal Nature Communications that they found that many people with short or bent forearms have a chromosomal rearrangement involving a collection of genes known as the HOXD gene cluster, which is activated during embryonic development in different parts of the body to regulating how cells and tissue become specialized. None of the individuals, however, had a mutation affecting the HOXD genes themselves.

That suggests that the deformities resulted from mutations that interfere with the regulation of HOXD gene expression during development, said Denis Duboule, a professor of Developmental Genetics and Genomics at EPFL and a corresponding author on the paper.

Christopher Chase Bolt, a postdoc in Duboule’s lab and lead author of the paper, studied mice to try to uncover what was happening during embryonic development to cause mesomelic dysplasias.

In the DNA, HOX genes line up in the same order as they are expressed in a developing embryo: first, the genes that regulate the formation of the shoulder; then, those that orchestrate the development of the arm; finally, those that guide the emergence of the hand and digits. Working in mice, Bolt created a chromosomal rearrangement that inverts the orientation of the HOXD cluster.

As a result of this inversion, the last gene of the cluster, called HOX13—which regulates the formation of the hand and digits, is located where the gene that orchestrates the development of the forearm typically is. Mice with this chromosomal rearrangement express HOX13 earlier during development than do control mice, and the researchers found they display a mild form of mesomelic dysplasia. That’s because HOX13 signals that the limb has reached its end and must stop growing, Bolt said. Having the gene expressed too early leads to extremely short extremities.

Next, Bolt and his colleagues used a CRISPR-Cas9 gene-editing technique to engineer mice that had an inverted HOXD cluster but lacked the HOX13 gene. These animals did not have any limb deformities, suggesting that the faulty regulation of HOX13 expression is the main culprit for mesomelic dysplasia.

“When you invert the cluster, HOX13 is expressed in the forearm and it results in mesomelic dysplasia,” Duboule said. “But when you kill the gene, you get no problem—you actually rescue the phenotype.”

Because HOX genes are remarkably similar across disparate animals—from fruit flies to mice to humans, the findings have relevance for many people with mesomelic dysplasia. Indeed, the mechanism identified offers a molecular explanation for all cases of human mesomelic dysplasias involving HOX genes reported so far, Duboule said.

Author: Rare Daily Staff

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