Jax researchers collaborate to find novel genes required for left-right asymmetry in vertebrates

The left­-right axis along the body (laterality) is defined early in embryogenesis, and it is necessary for proper positioning of visceral organs (for instance, the heart and spleen sit on the left side, and the liver on the right). In humans, loss of laterality is called heterotaxy, a rare disorder affecting approximately 1 in every 10,000 babies born. Heterotaxy is often discovered soon after birth because it is frequently associated with congenital heart defects. In addition to altering the location of organs within the body, heterotaxy can also affect the development of the liver, lungs, intestines and spleen. Medication and surgery can stabilize many of the medical problems that arise from this disorder, but length and quality of life can be severely compromised depending on the specific anatomy of the patient.   

In an article published in Nature Genetics in November, Candice Baker and Stephen Murray of JAX Bar Harbor were members of a team investigating genes that may be responsible for heterotaxy in humans. To reduce the noise generated from normal person-to-person genetic variation, the team first looked at the genomes of two families with multiple children affected by the disease. They found that the affected children had mutations in both alleles of the gene MMP21. MMP21 is a member of the matrix metalloproteinase family, a group of enzymes that breakdown extracellular matrix (ECM, the molecular scaffold that surrounds and supports cells in the body). MMPs were known to important in embryonic development, because ECM remodeling is necessary for tissue growth and morphogenesis. However, their importance in defining left-right asymmetry was not previously appreciated.

To confirm the link between mutations in MMP21 and heterotaxy, the team transferred the suspected disease-inducing alleles into fish and mouse embryos using morpholinos and CRISPR/Cas9 technology, respectively. They discovered that the mutant alleles induce heart defects in both animals, and more that half the mice tested displayed altered laterality of visceral organs. Therefore, MMP21 has an essential role in specifying left-right asymmetry in these animals as well.

Interestingly, when the team analyzed the published genomes of other animals, they found that MMP21 was either absent or undergoing decay in reptiles, birds and cetartiodactyl mammals (such as pigs), suggesting that laterality in these vertebrates is defined independently of MMP21. Therefore, understanding how left-right asymmetry is defined in these animals may provide clues for novel therapeutics for human heterotaxy syndromes.