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

Nat Genet. 2009 Jan;41(1):106-11. doi: 10.1038/ng.278.

Chantal Lagresle-Peyrou ¹, Emmanuelle M Six, Capucine Picard, Frédéric Rieux-Laucat, Vincent Michel, Andrea Ditadi, Corinne Demerens-de Chappedelaine, Estelle Morillon, Françoise Valensi, Karen L Simon-Stoos, James C Mullikin, Lenora M Noroski, Céline Besse, Nicolas M Wulffraat, Alina Ferster, Manuel M Abecasis, Fabien Calvo, Christine Petit, Fabio Candotti, Laurent Abel, Alain Fischer, Marina Cavazzana-Calvo

Affiliations

Affiliation

1 Research Laboratory on Normal and Pathologic Development of the Immune System, U768, Institut National de la Santé et de la Recherche Médicale, 75015 Paris, France.

PMID: 19043416 DOI: 10.1038/ng.278

Abstract

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.

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