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

The Journal of Clinical Investigation
Claire R HughesLouise A Metherell

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. ...Continue Reading

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Citations

Feb 23, 2012·The Journal of Clinical Investigation·Laure GineauEmmanuelle Jouanguy
Feb 23, 2012·The Journal of Clinical Investigation·Jordan S Orange
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Methods Mentioned

BETA
genotyping
Exome Sequencing
PCR
gene knockout
restriction digest
gradient density centrifugation
FCS
transfections
transfection
in vitro transcription

Software Mentioned

Leica
DCViewer
MAQ
IBDfinder
Ensembl

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