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

Content Provider	PubMed Central
Author	Laure, Gineau Céline, Cognet Kara, Nihan Lach, Francis Peter Dunne, Jean Uma, Veturi Picard, Capucine Trouillet, Céline Céline, Eidenschenk Said, Aoufouchi Alexandre, Alcaïs Smith, Owen Geissmann, Frédéric Feighery, Conleth Abel, Laurent Agata, Smogorzewska Stillman, Bruce Vivier, Eric Casanova, Jean-laurent Emmanuelle, Jouanguy
Copyright Year	2012
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 CD56dim 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 CD56dim subset in patients was associated with a lower rate of NK CD56bright cell proliferation, and the maturation of NK CD56bright cells toward an NK CD56dim 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.
Related Links	http://dx.doi.org/10.1172/jci61014
Ending Page	832
Page Count	12
Starting Page	821
File Format	PDF
ISSN	00219738
e-ISSN	15588238
Journal	The Journal of Clinical Investigation
Issue Number	3
Volume Number	122
Language	English
Publisher	American Society for Clinical Investigation
Publisher Date	2012-03-01
Access Restriction	Open
Rights Holder	American Society for Clinical Investigation
Subject Keyword	Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Medicine

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
2	Indian Institute of Technology Kharagpur	Host Institute of the Project: The host institute of the project is responsible for providing infrastructure support and hosting the project	https://www.iitkgp.ac.in
3	National Digital Library of India Office, Indian Institute of Technology Kharagpur	The administrative and infrastructural headquarters of the project	Dr. B. Sutradhar bsutra@ndl.gov.in
4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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