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

Nature Genetics volume 41, pages 106–111 (2009)Cite this article

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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Figure 1: AK2 gene mutations in seven individuals with reticular dysgenesis.
Figure 2: Gene and protein expression analysis of AK2 in cell lines derived from individuals with reticular dysgenesis.
Figure 3: Complementation of the neutrophil differentiation defect by restoration of AK2 expression.
Figure 4: AK2 distribution in the mouse inner ear.

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Acknowledgements

We wish to thank the Antoine Béclère Hospital and the Pitié-Salpetrière Hospital for providing cord blood samples, the French National Genotyping Centre for contributing to the genome-wide linkage scan and P. Cherukuri and the NISC Comparative Sequencing Program (NISC, National Human Genome Research Institute, National Institutes of Health) for their help in sequencing the region of interest. We are grateful to I. André-Schmutz, S. Blanche, J.L. Casanova, J. Chinen, C. Chomienne, L. Coulombel, L. dal Cortivo, F. Le Deist, G. de Saint-Basile and J.P. de Villartay for discussions and assistance, and to all staff nurses who cared for the patients. We also thank the subjects' families for their participation. We acknowledge C. Hue, C. Martinache, J. Rouiller, C. Soudais and M.C. Stolzenberg for their technical assistance, as well as D. Fraser for his language editing review. The study was funded by the French National Institute for Health and Medical Research (INSERM), the French Institute for Rare Diseases (GIS-Institut des maladies rares), the French National Research Agency (ANR) and the Intramural Research Program of the National Human Genome Research Institute (NIH).

Author information

Author notes

  1. Chantal Lagresle-Peyrou and Emmanuelle M Six: These authors contributed equally to this work.

  2. Laurent Abel and Alain Fischer: These authors contributed equally to this work.

Authors and Affiliations

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

    Chantal Lagresle-Peyrou, Emmanuelle M Six, Capucine Picard, Frédéric Rieux-Laucat, Andrea Ditadi, Corinne Demerens-de Chappedelaine, Estelle Morillon, Françoise Valensi, Alain Fischer & Marina Cavazzana-Calvo

  2. Université Paris Descartes, Faculté de Médecine, IFR94, Paris, 75015, France

    Chantal Lagresle-Peyrou, Emmanuelle M Six, Capucine Picard, Frédéric Rieux-Laucat, Andrea Ditadi, Corinne Demerens-de Chappedelaine, Estelle Morillon, Laurent Abel, Alain Fischer & Marina Cavazzana-Calvo

  3. Laboratoire d'Immunologie Cellulaire et Immunopathologie de l'Ecole Pratique des Hautes Etudes and UMR 7151 Centre National de la Recherche Scientifique Université Paris 7, Paris, 75015, France

    Chantal Lagresle-Peyrou

  4. Centre d'Étude des Déficits Immunitaires, Assistance Publique-Hôpitaux de Paris, Hôpital Necker-Enfants Malades, Paris, 75015, France

    Capucine Picard

  5. Laboratory of Human Genetics of Infectious Diseases, U550, Institut National de la Santé et de la Recherche Médicale, Paris, 75015, France

    Capucine Picard & Laurent Abel

  6. Unité de Génétique et Physiologie de l'Audition, UMRS587 INSERM-Université Paris VI, Institut Pasteur, Paris, 75015, France

    Vincent Michel & Christine Petit

  7. Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Karen L Simon-Stoos

  8. Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA

    James C Mullikin & Fabio Candotti

  9. Division of Allergy and Immunology, Department of Pediatrics, Baylor College of Medicine, Houston, 77030, Texas, USA

    Lenora M Noroski

  10. Centre National de Génotypage, Institut Génomique, Commissariat à l'Energie Atomique, Evry, 91000, France

    Céline Besse

  11. Department of Immunology/BMT, Wilhelmina Children's Hospital, Utrecht Medical Center, Utrecht, 3584 CX, The Netherlands

    Nicolas M Wulffraat

  12. Pediatric Hemato-Oncology Unit, Children's University Hospital Reine Fabiola, Brussels, 1020, Belgium

    Alina Ferster

  13. Bone Marrow Transplantation Unit, Portuguese Institute of Oncology Francisco Gentil, Lisboa, 1099-023, Portugal

    Manuel M Abecasis

  14. Clinical Investigation Center, INSERM U716, AP-HP, University Paris 7, Hôpital Saint-Louis, Paris, 75015, France

    Fabien Calvo

  15. Collège de France, 11 place Marcellin Berthelot, Paris, 75015, France

    Christine Petit

  16. AP-HP, Hôpital Necker-Enfants Malades, Service d'Immunologie et d'Hématologie Pédiatrique, Paris, 75015, France

    Alain Fischer

  17. Département de Biothérapie, AP-HP, Hôpital Necker-Enfants Malades, Paris, 75015, France

    Marina Cavazzana-Calvo

Authors
  1. Chantal Lagresle-Peyrou
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  2. Emmanuelle M Six
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Contributions

C.L.-P. and E.M.S. contributed equally to this study by performing most of the experimental work and analysis, with the assistance of C.D.-d.C. and E.M. C. Picard and F.R.-L. performed apoptotic tests on the fibroblasts, gave critical advice and comments in designing the experiments. Experiments shown in Figure 4 were performed by V.M. A.D. performed the RNA interference experiments. F.V. provided expertise in histological examination. K.L.S.-S. mapped P6 deletion and found P7 mutation. J.C.M. performed the sequencing project. C.B. performed the genome-wide linkage scan. C. Picard, L.M.N., N.M.W., A. Ferster, M.M.A. and M.C.-C. recruited and diagnosed the individuals with reticular dysgenesis and provided materials from them. F. Calvo gave critical comments in designing the experiments and helped to sequence the healthy and pathological samples. C. Petit contributed to the design of the inner ear experiments and F. Candotti designed and coordinated the sequencing project. C. Picard and L.A. performed the lod-score analysis. L.A. and A. Fischer contributed equally to this study. M.C.-C. supervised the overall project. M.C.-C., C.L.-P., E.M.S., L.A. and A. Fischer wrote the paper and added the comments from all authors.

Corresponding author

Correspondence to Marina Cavazzana-Calvo.

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Lagresle-Peyrou, C., Six, E., Picard, C. et al. Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nat Genet 41, 106–111 (2009). https://doi.org/10.1038/ng.278

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