TY - JOUR
T1 - Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency
AU - Gineau, Laure
AU - Cognet, Céline
AU - Kara, Nihan
AU - Lach, Francis Peter
AU - Dunne, Jean
AU - Veturi, Uma
AU - Picard, Capucine
AU - Trouillet, Céline
AU - Eidenschenk, Céline
AU - Aoufouchi, Said
AU - Alcaïs, Alexandre
AU - Smith, Owen
AU - Geissmann, Frédéric
AU - Feighery, Conleth
AU - Abel, Laurent
AU - Smogorzewska, Agata
AU - Stillman, Bruce
AU - Vivier, Eric
AU - Casanova, Jean Laurent
AU - Jouanguy, Emmanuelle
PY - 2012/3/1
Y1 - 2012/3/1
N2 - 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 dimphenotype 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.
AB - 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 dimphenotype 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.
UR - http://www.scopus.com/inward/record.url?scp=84857815874&partnerID=8YFLogxK
U2 - 10.1172/JCI61014
DO - 10.1172/JCI61014
M3 - Article
C2 - 22354167
AN - SCOPUS:84857815874
SN - 0021-9738
VL - 122
SP - 821
EP - 832
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 3
ER -