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.

Too much to handle — how gaining chromosomes destabilizes the genome

“…29 In humans, a recessive condition called Meier-Gorlin syndrome, which is caused by an N-terminal truncation of MCM4 leads to increased chromosomal fragility in patients' lymphocytes and dermal fibroblasts. 30,31 A similar phenotype of DNA breaks and gaps was also observed in human aneuploid cell lines. Indeed, we demonstrated that the low levels of MCM2-7 are responsible for the replication defects in aneuploids, as restoring near wild-type levels of MCM2-7 partially alleviated the phenotype.…”

Eight-color immunophenotyping of T-, B-, and NK-cell subpopulations for characterization of chronic immunodeficiencies

“…Moreover, a selective view on CD56, CD16, and CD56 bright subsets is also helpful for the diagnosis of patients with defects in the NK-cell system, including those with mutations in the MCM4 gene. In MCM4 deficiency, it has been shown that patient's NK cells feature a lower CD16 expression, a selective loss of the CD56 dim subset and a higher CD56 bright / CD56 dim ratio (62). Classically, a clinical diagnosis in chronic immunodeficiencies is preceded by a specific clinical suspicion and subsequent diagnostic tests.…”

NK cells and cancer: you can teach innate cells new tricks

“…50) or MCM4 (REF. 51), lead to higher rates of malignancy. These primary immunodeficiencies affecting NK cells indicate how important these cells are in tumour immune surveillance.…”