Mutations in the RNA component of RNase mitochondrial RNA processing might cause Omenn syndrome

BackgroundOmenn syndrome is a variant of severe combined immunodeficiency disease, which most prominently presents with erythroderma, eosinophilia, and susceptibility to various pathogens. Mutations in the nucleases of recombination activating genes 1 and 2 (RAG1/RAG2) or Artemis were found in some, but not all, patients with Omenn syndrome. We identified 2 patients who presented with clinical features consistent with Omenn syndrome but had no mutations in RAG or Artemis. Both patients also had cartilage-hair hypoplasia (CHH).ObjectivesWe sought to define the molecular basis and characterize the features of severe combined immunodeficiency and Omenn syndrome in these patients.MethodsWe have studied humoral and cellular immunity using standard assays. T-cell repertoire was investigated by quantitating Vβ families. The RNase mitochondrial RNA processing (RMRP) RNA gene was sequenced by using standard techniques.ResultsSequence analysis of the RMRP RNA gene showed that each patient had an insertion-duplication on one allele and a point mutation on the other allele. These point mutations were novel, and they might be related to the unusual presentation of Omenn syndrome in addition to CHH in these patients. Indeed, analysis of the thymus showed residual mature T lymphocytes. This leaky thymus might be responsible for the skewed release of some T-cell clones into the circulation, which might trigger the phenotype of Omenn syndrome.ConclusionWe have demonstrated that mutations in the RMRP RNA gene might be associated with Omenn syndrome.Clinical implicationsThis discovery will aid clinicians in the early recognition and treatment of CHH-associated Omenn syndrome.