Mutations in a single gene linked to two unrelated types of infections

By John Murphy, MDLinx
Published January 5, 2016

Key Takeaways

Researchers have identified how mutations in a single gene render certain children vulnerable to two very different diseases: aggravating, but treatable candidiasis, as well as invasive and potentially fatal mycobacteriosis.

In work published July 9 in Science, researchers reported the rare case of a 6-year-old child with disease caused by the tuberculosis vaccine. They discovered she had an immune system deficiency in which mutations in the gene RORC resulted in susceptibility to this mycobacteria.

“Over the years, my lab has found that inborn errors in the production of an immune system signaling molecule, or cytokine, called interferon-γ specifically impair the defenses against relatively harmless types of mycobacteria, such as the live tuberculosis vaccine,” said Jean-Laurent Casanova, MD, PhD, head of the St. Giles Laboratory of Human Genetics of Infectious Disease at Rockefeller University Hospital in New York, and investigator at Howard Hughes Medical Institute in Chevy Chase, MD. “Our experiments have shown that mutations in RORC give rise to multiple problems within the immune system, including interfering with the production of interferon-γ, which is crucial for fending off mycobacteria.”

As in this investigation, Dr. Casanova’s lab works with physicians in centers around the world to collect samples from patients who suffer from such mycobacterial infections. His lab then searches these patients’ genetic sequences for the mutations responsible for this vulnerability.

The researchers found that this child carried two mutated copies of RORC—a gene that helps control the development of interleukin-17-producing T cells, which is important for host defense against Candida.

“The RORC mutations seemed to explain the child’s thrush,” said Satoshi Okada, MD, PhD, who was then a post-doc in Dr. Casanova’s lab and is now assistant professor of pediatrics at Hiroshima University Graduate School of Biomedical & Health Sciences in Japan. “But I was skeptical that these could be linked to the BCG [mycobacterial] infection that ultimately caused her death. However, after two other children in her extended family contracted similar infections, I found sets of RORC mutations in each, strongly suggesting a connection to the illnesses.”

The child’s parents were first cousins, the investigators learned. Subsequently, the researchers confirmed the link between RORC and the mycobacterial vulnerability in the genomes of one Chilean and three Saudi children, who were also the offspring of consanguineous marriages and who suffered from a similar combination of diseases.

The researchers verified that the RORC mutations found in the patients dramatically decreased their ability to produce interleukin-17. They also pinned down a connection to interferon-γ, and as a result, mycobacterial disease.

“While Candida infections can be treated with anti-fungal medications, mycobacterial disease can be life-threatening,” Dr. Casanova said. “Our results show that patients who suffer from mycobacterial infections as a result of RORC mutations can be treated with interferon-γ—a potentially life-saving intervention. By finding that RORC helps control the development of these two cytokines, interleukin-17 and interferon-γ, we have revealed a surprisingly dual role for RORC in human immunity to infection.”

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