Multitude effects of MCM4 mutation

Two recent studies (J. Clin. Invest. 122, 814–820; J. Clin. Invest. 122, 821–832) discover the underlying molecular defect responsible for a variant of familial glucocorticoid deficiency, identifying it as a new DNA replication disorder and providing mechanistic insights into the disease phenotype.

In two independent studies, Claire Hughes et al. and Laure Gineau et al.identified the causative mutation in the minichromosome maintenance-deficient 4 gene (MCM4) of affected individuals. The responsible MCM4 mutation is located in a splice site, leading to the production of a protein truncated at the N-terminal domain. MCM4 is a component of a helicase complex required for DNA replication. Gineau et al. found no defects in the formation of this complex in fibroblasts from people with MCM4 mutations, but observed high levels of rereplication and DNA breakage in these cells, suggesting that truncation of the N-terminal domain of MCM4 affects DNA replication and genome integrity.

Individuals with MCM4 mutation show a phenotype consistent with other DNA repair and replication disorders, with chromosomal fragility, growth retardation and a variable degree of immunodeficiency. This immunodeficiency seems to result from a natural killer (NK) cell deficiency, as Gineau et al. showed that the subjects had a selective deficiency in the CD56^dim subset of NK cells, which are the major form of mature circulating NK cells. It remains to be seen whether individuals with MCM4 mutation have an increased risk of cancer, because neither team detected any cancers in the subjects they examined. In addition, the affected individuals show adrenal insufficiency, and Hughes et al. showed that mice depleted for Mcm4 also had abnormal adrenal morphology.

The results of these two studies are particularly interesting in light of the recent identification of mutations in components of the prereplicative complex in another growth retardation disorder, Meier-Gorlin syndrome. This first identification of a human mutation in MCM4 may spur investigation into other MCM complex components as candidate disease genes.