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

J Clin Invest. 2012 Mar;122(3):814-20. doi: 10.1172/JCI60224. Epub 2012 Feb 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenal Insufficiency / genetics*
  • Animals
  • Body Height
  • Cell Cycle Proteins / genetics*
  • DNA Helicases / genetics*
  • DNA-Binding Proteins / genetics*
  • Female
  • Genotype
  • HEK293 Cells
  • Humans
  • Killer Cells, Natural / cytology*
  • Male
  • Mice
  • Minichromosome Maintenance Complex Component 4
  • Mutation*
  • Nuclear Proteins / genetics*
  • Pedigree
  • Phenotype
  • Protein Isoforms
  • Sequence Analysis, DNA


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Protein Isoforms
  • DNA Helicases
  • MCM4 protein, human
  • Mcm4 protein, mouse
  • Minichromosome Maintenance Complex Component 4