title: 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.affiliation: 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.
authors.forename: Chantal
authors.initials: C
authors.lastname: Lagresle-Peyrou
authors.forename: Emmanuelle M
authors.initials: EM
authors.lastname: Six
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rieux-Laucat
authors.forename: Vincent
authors.initials: V
authors.lastname: Michel
authors.forename: Andrea
authors.initials: A
authors.lastname: Ditadi
authors.forename: Corinne
authors.initials: C
authors.lastname: Demerens-de Chappedelaine
authors.forename: Estelle
authors.initials: E
authors.lastname: Morillon
authors.forename: Françoise
authors.initials: F
authors.lastname: Valensi
authors.forename: Karen L
authors.initials: KL
authors.lastname: Simon-Stoos
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.forename: Lenora M
authors.initials: LM
authors.lastname: Noroski
authors.forename: Céline
authors.initials: C
authors.lastname: Besse
authors.forename: Nicolas M
authors.initials: NM
authors.lastname: Wulffraat
authors.forename: Alina
authors.initials: A
authors.lastname: Ferster
authors.forename: Manuel M
authors.initials: MM
authors.lastname: Abecasis
authors.forename: Fabien
authors.initials: F
authors.lastname: Calvo
authors.forename: Christine
authors.initials: C
authors.lastname: Petit
authors.forename: Fabio
authors.initials: F
authors.lastname: Candotti
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Marina
authors.initials: M
authors.lastname: Cavazzana-Calvo
mesh_terms: D000263:Adenylate Kinase / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D007758:Ear, Inner / Q000201:enzymology / Q000473:pathology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006319:Hearing Loss, Sensorineural / Q000150:complications* / Q000201:enzymology* / Q000235:genetics; D006413:Hematopoietic System / Q000473:pathology*; D006801:Humans; D007231:Infant, Newborn; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics; D009504:Neutrophils / Q000473:pathology; D010375:Pedigree; D021381:Protein Transport; D016511:Severe Combined Immunodeficiency / Q000150:complications / Q000201:enzymology / Q000235:genetics / Q000276:immunology
chemical_list: D007527:Isoenzymes; D000263:Adenylate Kinase; C110938:adenylate kinase 2