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

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.

• Authors: Chantal Lagresle-Peyrou, 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
• Journal: Nature genetics (Nat Genet) Vol. 41 Issue 1 Pg. 106-11 (Jan 2009) ISSN: 1546-1718 [Electronic] United States
• PMID: 19043416 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Isoenzymes
• Adenylate Kinase
• adenylate kinase 2

Topics

• Adenylate Kinase (deficiency, genetics, metabolism)
• Animals
• Cell Differentiation
• Cell Line
• Ear, Inner (enzymology, pathology)
• Female
• Gene Expression Regulation, Enzymologic
• Hearing Loss, Sensorineural (complications, enzymology, genetics)
• Hematopoietic System (pathology)
• Humans
• Infant, Newborn
• Isoenzymes (deficiency, genetics, metabolism)
• Male
• Mice
• Mutation (genetics)
• Neutrophils (pathology)
• Pedigree
• Protein Transport
• Severe Combined Immunodeficiency (complications, enzymology, genetics, immunology)