Researchers identify genetic variations that cause rare, deadly illness

TOKYO: Many illnesses are caused by genetic variants; worse, the genetic origin of the majority of ailments is unknown.

Researchers have shed light on the specific variations responsible for an uncommon and deadly condition known as 'RAD50 deficiency/Nijmegen breakage syndrome-like disorder' in a study published recently in the Journal of Clinical Immunology.

RAD50, along with MRE11 and NBN, is one of three proteins that make up the 'MRN complex,' which recognises DNA breaks and helps to initiate DNA repair.

Because each of the three proteins is encoded by a distinct gene, changes in any of the three genes can cause the MRN complex to malfunction.

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."