Discovery of a gene associated with a set of poorly understood rare diseases

IRB Barcelona identifies GEMC1 as a master gene for the generation of multiciliated cells – cells with fine filaments that move fluids and substances – which are found exclusively in the brain, respiratory tract, and reproductive system.

Defects in multiciliated cells lead to ciliopathies – rare and complex diseases that are poorly understood and for which not all causative genes have been identified.

The genomic sequencing of hundreds of patients with diverse types of ciliopathies has revealed that “in many cases the gene responsible is not known”, says Travis Stracker, head of the Genomic Instability and Cancer Lab at the IRB Barcelona. “So many people do not have a molecular diagnosis,” stresses the researcher. “Our work seeks to contribute to bridging this knowledge gap”.

Images of mouse tracheas
GEMC1 is required for the generation of multiciliated cells. Images of mouse tracheas. The cilia (yellow) are clearly evident in the wild-type mice and absent in mice with no GEMC1
Image Credit: Berta Terré, IRB Barcelona

The EMBO Journal has published a study on mice by Travis Stracker and his team, in collaboration with Vincenzo Costanzo’s laboratory at the FIRC Institute of Molecular Oncology (IFOM) in Milan, in which they reveal a gene candidate for a subtype of human ciliopathy. The gene in question, GEMC1, is indispensable for the generation of multiciliated cells specific to tissues such as the brain, trachea, lungs and oviducts.

The surface of multiciliated cells is covered by hundreds of cilia. These tiny, hairlike structures serve to circulate cerebrospinal fluid, remove mucus from the respiratory tract, and transport ovum through the oviduct, among other functions. Defects in the generation or function of these cells causes a subtype of ciliopathies called Mucociliary Clearance Disorders.

Candidate and master gene

Specifically, GEMC1-deficient mice produced by Stracker reproduce the symptoms of a rare disease called RGMC (Reduced Generation of Multiple Motile Cilia)- a condition that causes hydrocephaly, severe respiratory infections, and infertility. The work, led by IRB Barcelona PhD student Berta Terré and IFOM postdoctoral researcher Gabriele Piergiovanni, reports that GEMC1 regulates the only two genes known to date that underlie this disease, Multicilin and Cyclin O, thus making it a potential candidate gene for RGMC.

In addition, the study has revealed that GEMC1 is one of the most important genes in the gene signalling cascade for the production of multiciliated cells. This means that this gene affects many others that depend on its expression. The gene expression analysis of this first study has revealed at least 10 new candidate genes related to cilia, as well as dozens that were already known or suspected of being involved in the function of cilia.

“The mice are a particular model of RGMC but we believe that this model will allow us to identify many new genes involved in motile cilia, which affect other types of ciliopathies. We are now performing new gene expression analyses of specific cell populations to shed more light on a field about which little is known,” says Stracker, who studied GEMC1 because of its function in DNA replication and potential contribution to cancer.

“While examining this gene for other reasons, we unexpectedly found it was potentially involved in ciliopathies. This kind of thing often happens in basic research and for us it was really interesting because of the lack of knowledge regarding these diseases and the biomedical implications our findings may have,” explains Stracker. “As ciliopathies are diverse and rare diseases, they have not received widespread attention from funding agencies and the pharma industry, as they are not interested in developing treatments for small markets, which is a great shame,” chides the researcher.

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