MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans

Abstract

An interesting variant of familial glucocorticoid deficiency (FGD), an autosomal recessive form of adrenal failure, exists in a genetically isolated Irish population. In addition to hypocortisolemia, affected children show signs of growth failure, increased chromosomal breakage, and NK cell deficiency. Targeted exome sequencing in 8 patients identified a variant (c.71-1insG) in minichromosome maintenance-deficient 4 (MCM4) that was predicted to result in a severely truncated protein (p.Pro24ArgfsX4). Western blotting of patient samples revealed that the major 96-kDa isoform present in unaffected human controls was absent, while the presence of the minor 85-kDa isoform was preserved. Interestingly, histological studies with Mcm4-depleted mice showed grossly abnormal adrenal morphology that was characterized by non-steroidogenic GATA4-and Gli1-positive cells within the steroidogenic cortex, which reduced the number of steroidogenic cells in the zona fasciculata of the adrenal cortex. Since MCM4 is one part of a MCM2-7 complex recently confirmed as the replicative helicase essential for normal DNA replication and genome stability in all eukaryotes, it is possible that our patients may have an increased risk of neoplastic change. In summary, we have identified what we believe to be the first human mutation in MCM4 and have shown that it is associated with adrenal insufficiency, short stature, and NK cell 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.…”

The MCM and RecQ Helicase Families: Ancient Roles in DNA Replication and Genomic Stability Lead to Distinct Roles in Human Disease

“…A human MCM4 mutation (destabilizing the MCM2-7 complex) was recently reported concurrently by two groups who studied consanguineous families, and the resulting phenotype was found to be associated with immune deficiency (NK cells), adrenal insufficiency and short stature [79,80]. Patient fibroblasts showed chromosome fragility [79].…”

“…Patient fibroblasts showed chromosome fragility [79]. The susceptibility of these patients to cancer is not currently known [80]. An MCM8 disruption and alternative splice form have been noted in hepatic carcinoma [11] and choriocarcinoma [12], respectively.…”

Melanocortin receptors and their accessory proteins

“…Recently, mutations in nicotinamide nucleotide transhydrogenase (NNT) a mitochondrial membrane constituent which is involved in detoxification of reactive oxygen species were also associated with FGD . Notably, mutations in minichromosome maintenance-deficient 4 (MCM4) which forms part of a protein complex which is essential for DNA replication and genome stability are associated with a variant of FGD found in the Irish Traveller population where adrenal failure is accompanied by short stature, chromosome instability, and natural killer cell dysfunction (O'Riordan et al, 2008;Gineau et al, 2012;Hughes et al, 2012).…”