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

Abstract

Corresponding author: m.cavazzana@nck.aphp.fr, Professor Marina Cavazzana-Calvo, Biotherapy Department, Hopital Necker EnfantsMalades, 149 rue de Sevres, F-75015 Paris, France; tel. +33 1 44 49 50 68; fax +33 1 44 49 25 05. 18 These authors contributed equally to this work 19 These authors contributed equally to this work Author 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.-C. and E.M. C.Picard and F.R.-L. performed apoptotic tests on the fibroblasts, gave critical advices and comments in designing the experiments. Experiments shown in Fig. 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.F., M.M.A. and M.C.-C. recruited and diagnosed the RD patients and provide materials for 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, F.Candotti designed and coordinated the sequencing project. C. Picard and L.A. performed the Lodscore analysis. L.A. and A.F. 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.F. wrote the paper and added the comments from all authors. Author information: All authors declare that there is no competing financial interests. Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. Correspondence and requests for materials should be addressed to Marina Cavazzana-Calvo (m.cavazzana@nck.aphp.fr). NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2010 January 1. Published in final edited form as:Nat Genet. We have identified biallelic mutations in the adenylate kinase 2 (AK2) gene in seven patients affected with RD. These mutations resulted in the absence or a strong decrease in protein expression. We then demonstrated that restoration of AK2 expression in the bone marrow cells of RD patients overcomes the neutrophil differentiation arrest underlining 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, which provides an explanation to the sensorineural deafness. These results suggest a novel mechanism regulating haematopoetic cell differentiation, and involved in one of the most severe human immunodeficiency syndromes.The term "reticular dysgenesis" (RD), was coined in 1959 by de Vall and Seyneheve 1 and relates to the histological findings in primary and secondary lymphohaematopoietic organs, where the scarcity of cells highlights the prominent reticular tissue framework. The lack of polymorphonuclear neutrophils (PMNs) in affected patien...

Reticular dysgenesis–associated AK2 protects hematopoietic stem and progenitor cell development from oxidative stress

“…et al, 2000,2002). Impairment of AK2 activity in humans leads to the severe lymphocyte and granulocyte differentiation defects and sensorineural deafness characteristic for RD (Lagresle-Peyrou et al, 2009;Pannicke et al, 2009). Our studies in zebrafish and iPSCs show that AK2 deficiency is associated with an even broader hematological phenotype than originally anticipated, which affects the development of the erythroid lineage, in addition to the known abnormalities in granulocyte and lymphocyte differentiation.…”

Adenylate Kinase 2 Links Mitochondrial Energy Metabolism to the Induction of the Unfolded Protein Response

“…AK2 gene mutations have been recently identified as the cause of reticular dysgenesis, a rare form of human severe combined immunodeficiency in humans (26,27). Individuals with reticular dysgenesis are almost completely lacking in mature lymphoid cells as well as granulocytes.…”

“…We find that although impairment in oxidative phosphorylation has little effect, AK2 depletion strongly compromises the induction of the UPR in adipocytes, and more so in B cells, which represent professional secretory cells. These results reveal a novel mechanism by which mitochondrial energy metabolism and ER homeostasis are linked, which may explain the profound hematopoietic defects associated both with UPR deficiency (30) and with genetic deficiency of AK2 (26,27).…”

“…The single isoform of adenylate kinase present in bacteria and lower eukaryotes is essential for life (22)(23)(24), and AK2 is required for Drosophila development (25). Moreover, mutations in AK2 are the basis for a profound failure of lymphopoiesis in humans (26,27). Based on these precedents, the induction of AK2 with adipocyte differentiation may signify an important role for this enzyme in energy homeostasis in the mature adipocyte.…”

Limb girdle myasthenia with digenic RAPSN and a novel disease gene AK9 mutations

“…37 Three AKs are now known to be associated with disease phenotypes, AK1 (OMIM 103000) causes chronic hemolytic anemia in humans, 38 AK2 (OMIM 267500) causes reticular dysgenesis in humans, 39 and AK7 (OMIM 615364) with primary ciliary dyskinesia in mice. 40 AK1, like AK9, is cytosolic and associated with mental retardation and psychomotor retardation.…”