Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency

Laboratory of Human Genetics of Infectious Diseases, Necker Branch, Institut National de la Santé et de la Recherche Médicale U980, Paris, France.
The Journal of clinical investigation (Impact Factor: 13.22). 03/2012; 122(3):821-32. DOI: 10.1172/JCI61014
Source: PubMed


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.

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    • "This patient later developed a bone marrow failure shown to be caused by GATA-2 mutation (Mace et al., 2013). Patients presenting with isolated NK cell deficiency, adrenal insufficiency and herpesvirus susceptibility were shown to carry MCM4 autosomal recessive mutations, a gene involved in DNA replication (Gineau et al., 2012). Recently, a patient presenting an isolated NK cell deficiency, who died from VZV infection, was reported to carry a known founder mutation in RTEL1, a gene involved in telomere maintenance (Hanna et al., 2015). "

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    • "Mice with reduced DOs show genomic instability, age-related dysfunction, and develop tumors (Kunnev et al., 2010; Pruitt et al., 2007; Shima et al., 2007). Importantly, congenital hypomorphic MCM4 defects have been found in humans, associated with various abnormalities and elevated genomic instability (Gineau et al., 2012; Hughes et al., 2012). Despite the importance of DOs, it is unknown whether they exist and function differently in stem cells. "
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    ABSTRACT: Maintaining genomic integrity during DNA replication is essential for stem cells. DNA replication origins are licensed by the MCM2-7 complexes, with most of them remaining dormant. Dormant origins (DOs) rescue replication fork stalling in S phase and ensure genome integrity. However, it is not known whether DOs exist and play important roles in any stem cell type. Here, we show that embryonic stem cells (ESCs) contain more DOs than tissue stem/progenitor cells such as neural stem/progenitor cells (NSPCs). Partial depletion of DOs does not affect ESC self-renewal but impairs their differentiation, including toward the neural lineage. However, reduction of DOs in NSPCs impairs their self-renewal due to accumulation of DNA damage and apoptosis. Furthermore, mice with reduced DOs show abnormal neurogenesis and semi-embryonic lethality. Our results reveal that ESCs are equipped with more DOs to better protect against replicative stress than tissue-specific stem/progenitor cells. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Stem Cell Reports 07/2015; 5(2). DOI:10.1016/j.stemcr.2015.06.002 · 5.37 Impact Factor
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    • "A set of human patients that present with natural killer cell deficiency, growth retardation, adrenal insufficiency, and genome instability were recently shown to harbour a mutation resulting in expression of a truncated form of MCM4 [15,34,38]. Though this truncated form does not seem to affect loading of the helicase onto DNA, cells from these patients exhibit increased levels of chromosome breakage as well as a defective cell cycle. "
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    ABSTRACT: The ability of a eukaryotic cell to precisely and accurately replicate its DNA is crucial to maintain genome stability. Here we describe our current understanding of the process by which origins are licensed for DNA replication and review recent work suggesting that fork stalling has exerted a strong selective pressure on the positioning of licensed origins. In light of this, we discuss the complex and disparate phenotypes observed in mouse models and humans patients that arise due to defects in replication licensing proteins.
    DNA repair 04/2014; 19(100). DOI:10.1016/j.dnarep.2014.03.012 · 3.11 Impact Factor
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