title: Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency.
abstract: Natural killer (NK) cells are circulating cytotoxic lymphocytes that exert potent and nonredundant antiviral activity and antitumoral activity in the mouse; however, their function in host defense in humans remains unclear. Here, we investigated 6 related patients with autosomal recessive growth retardation, adrenal insufficiency, and a selective NK cell deficiency characterized by a lack of the CD56(dim) NK subset. Using linkage analysis and fine mapping, we identified the disease-causing gene, MCM4, which encodes a component of the MCM2-7 helicase complex required for DNA replication. A splice-site mutation in the patients produced a frameshift, but the mutation was hypomorphic due to the creation of two new translation initiation methionine codons downstream of the premature termination codon. The patients' fibroblasts exhibited genomic instability, which was rescued by expression of WT MCM4. These data indicate that the patients' growth retardation and adrenal insufficiency likely reflect the ubiquitous but heterogeneous impact of the MCM4 mutation in various tissues. In addition, the specific loss of the NK CD56(dim) subset in patients was associated with a lower rate of NK CD56(bright) cell proliferation, and the maturation of NK CD56(bright) cells toward an NK CD56(dim) phenotype was tightly dependent on MCM4-dependent cell division. Thus, partial MCM4 deficiency results in a genetic syndrome of growth retardation with adrenal insufficiency and selective NK deficiency.
authors.affiliation: Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U980, Paris, France.
authors.forename: Laure
authors.initials: L
authors.lastname: Gineau
authors.forename: Céline
authors.initials: C
authors.lastname: Cognet
authors.forename: Nihan
authors.initials: N
authors.lastname: Kara
authors.forename: Francis Peter
authors.initials: FP
authors.lastname: Lach
authors.forename: Jean
authors.initials: J
authors.lastname: Dunne
authors.forename: Uma
authors.initials: U
authors.lastname: Veturi
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Céline
authors.initials: C
authors.lastname: Trouillet
authors.forename: Céline
authors.initials: C
authors.lastname: Eidenschenk
authors.forename: Said
authors.initials: S
authors.lastname: Aoufouchi
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcaïs
authors.forename: Owen
authors.initials: O
authors.lastname: Smith
authors.forename: Frédéric
authors.initials: F
authors.lastname: Geissmann
authors.forename: Conleth
authors.initials: C
authors.lastname: Feighery
authors.forename: Laurent
authors.initials: L
authors.lastname: Abel
authors.forename: Agata
authors.initials: A
authors.lastname: Smogorzewska
authors.forename: Bruce
authors.initials: B
authors.lastname: Stillman
authors.forename: Eric
authors.initials: E
authors.lastname: Vivier
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
mesh_terms: D000309:Adrenal Insufficiency / Q000235:genetics*; D000483:Alleles; D000818:Animals; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004265:DNA Helicases / Q000172:deficiency / Q000235:genetics*; D004261:DNA Replication; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006130:Growth Disorders / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007223:Infant; D007694:Killer Cells, Natural / Q000166:cytology*; D051379:Mice; D064148:Minichromosome Maintenance Complex Component 4; D009154:Mutation; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D010375:Pedigree
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D004265:DNA Helicases; C099243:MCM4 protein, human; C516793:Mcm4 protein, mouse; D064148:Minichromosome Maintenance Complex Component 4