Researchers find genetic variants linked to uncommon, deadly illness

TOKYO: To make matters worse, most diseases have unknown genetic origins. Genetic variants are the source of many illnesses. A recent study published in the Journal of Clinical Immunology has provided light on the particular alterations causing a rare and fatal ailment called 'RAD50 deficiency/Nijmegen breakage syndrome-like disorder'.

The 'MRN complex,' comprising RAD50, MRE11, and NBN, is a trio of proteins that detects breaks in DNA and facilitates the initiation of repair. Since each of the three proteins is encoded by a different gene, mutations in any one of the three genes may result in an abnormality affecting the MRN complex. However, whereas MRE11 and NBN gene variants are known to induce various illnesses, such as ataxia telangiectasia-like condition and Nijmegen breakage syndrome, the pathogenic implications of RAD50 gene variants have remained fairly unknown - until now.

"When we looked at the literature, we realized that only three cases of RAD50 deficiency, which leads to symptoms similar to those of Nijmegen breakage syndrome, had been reported," explained Masatoshi Takagi, lead author of the study. "Of these three, just one was reported to have RAD50 variants, with associated bone marrow failure and immunodeficiency."

When the research team came across a patient with progressive bone marrow failure and immunodeficiency combined with Nijmegen breakage syndrome-like manifestations, they decided to perform whole-exome sequencing to see if they could identify any gene variants that might lead to the observed symptoms. "We found two different RAD50 variants in our patient, each of which was inherited from one of her parents," stated Takagi.

"We then tested the functional effects of these combined variants using fibroblast cells from the patient, which we grew in the lab." The functional experiments suggested that the patient's RAD50 variants led to a loss of function of the RAD50 protein, and thus of the MRN complex. They also resulted in slower cell replication (i.e., mitosis), as expected. Interestingly, however, these variants did not cause hypersensitivity to radiation, unlike other known RAD50 variants.

"Together, the findings from our case and the three previously reported cases suggest that RAD50 deficiency/Nijmegen breakage syndrome-like disorder is characterized by growth retardation and microcephaly, which may coexist with bone marrow failure and immunodeficiency in some patients," said senior author of the study Hirokazu Kanegane. "This disorder may therefore increase susceptibility to infectious diseases and immune-related conditions."