Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness

Abstract

Marina Cavazzana-Calvo and colleagues report mutations in the gene encoding mitochondrial adenylate kinase 2 in reticular dysgenesis, the most severe form of inborn combined immunodeficiency, characterized by the absence of granulocytes and almost complete deficiency of lymphocytes in peripheral blood. Reticular dysgenesis is an autosomal recessive form of human severe combined immunodeficiency characterized by an early differentiation arrest in the myeloid lineage and impaired lymphoid maturation. In addition, affected newborns have bilateral sensorineural deafness. Here we identify biallelic mutations in AK2 (adenylate kinase 2) in seven individuals affected with reticular dysgenesis. These mutations result in absent or strongly decreased protein expression. We then demonstrate that restoration of AK2 expression in the bone marrow cells of individuals with reticular dysgenesis overcomes the neutrophil differentiation arrest, underlining its specific requirement in the development of a restricted set of hematopoietic lineages. Last, we establish that AK2 is specifically expressed in the stria vascularis region of the inner ear, which provides an explanation of the sensorineural deafness in these individuals. These results identify a previously unknown mechanism involved in regulation of hematopoietic cell differentiation and in one of the most severe human immunodeficiency syndromes.