Gineau, L., Cognet, C., Kara, N., Lach, F. P., Dunne, J., Veturi, U., Picard, C., Trouillet, C., Eidenschenk, C., Aoufouchi, S., Alcaïs, A., Smith, O., Geissmann, F., Feighery, C., Abel, L., Smogorzewska, A., Stillman, B., Vivier, E., Casanova, J. L., Jouanguy, E. (March 2012) Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. Journal of Clinical Investigation, 122 (3). pp. 821-832. ISSN 00219738 (ISSN)
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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.
| Item Type: | Paper |
|---|---|
| Subjects: | diseases & disorders > congenital hereditary genetic diseases bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function |
| CSHL Authors: | |
| Communities: | CSHL Cancer Center Shared Resources > Animal Services CSHL Cancer Center Shared Resources > DNA Sequencing Service CSHL Cancer Center Shared Resources > Flow Cytometry Service CSHL Cancer Center Shared Resources > Microscopy Service CSHL labs > Stillman lab CSHL Cancer Center Program > Gene Regulation and Cell Proliferation |
| Highlight: | Stillman, Bruce W. |
| Depositing User: | Matt Covey |
| Date: | March 2012 |
| Date Deposited: | 30 Jan 2013 21:52 |
| Last Modified: | 20 Jun 2017 16:27 |
| PMCID: | PMC3287233 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/26948 |
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