Human Adenylate Kinase 2 Deficiency Causes a Profound Haematopoietic Defect Associated with Sensorineural Deafness

Abstract

Abstract Human adenylate kinase 2 deficiency causes the most profound human haematopoietic defect associated with sensorineural deafness. Reticular dysgenesis (RD) is an autosomal recessive form of human severe combined immunodeficiency (SCID) characterized by an early differentiation block in the myeloid lineage and a profound impairment in lymphoid maturation associated with bilateral sensorineural deafness. The lack of polymorphonuclear neutrophils in affected newborns is responsible for the occurrence of severe infections earlier than usually observed in the other forms of SCID. Furthermore, RD associated neutropenia is characterized by the lack of responsiveness to G-CSF. We have identified bi-allelic mutations in the adenylate kinase 2 (AK2) gene is seven patients affected with RD. These mutations resulted in the absence or a strong decrease in protein expression. Restoration of AK2 expression in the bone marrow cells of RD patients overcomes the neutrophil differentiation arrest, underlying its specific requirement in the development of a restricted set of haematopoietic lineages. Lastly, we established that AK2 is specifically expressed in the stria vascularis region of the inner ear. The function of this gene in the differentiation of a given set of cell lineages is rapidly in progress, showing that studies of primary immunodeficiencies continue to provide key information on human lympho-haematopoietic development. Moreover the AK2 enzyme seems a key molecule in different biological systems such as the lympho-haematopoiesis and the brain development.