MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans
Claire R. Hughes, Leonardo Guasti, Eirini Meimaridou, Chen-Hua Chuang, John C. Schimenti, Peter J. King, Colm Costigan, Adrian J.L. Clark, Louise A. Metherell
Claire R. Hughes, Leonardo Guasti, Eirini Meimaridou, Chen-Hua Chuang, John C. Schimenti, Peter J. King, Colm Costigan, Adrian J.L. Clark, Louise A. Metherell
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Research Article

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.

Authors

Claire R. Hughes, Leonardo Guasti, Eirini Meimaridou, Chen-Hua Chuang, John C. Schimenti, Peter J. King, Colm Costigan, Adrian J.L. Clark, Louise A. Metherell

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Figure 3

Analysis of adrenals from MCM4 mutant mouse models.

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Analysis of adrenals from MCM4 mutant mouse models. (A–J) Adrenal cortic...
(A–J) Adrenal cortices of Mcm4Chaos3/–Mcm3+/– mice have an abnormal morphology. H&E staining of wild-type (A, B, and I), Mcm4Chaos3/+Mcm3+/– (C and D), and Mcm4Chaos3/–Mcm3+/– adrenals at 3.5 months (E and F) and Mcm4Chaos3/–Mcm3+/– at 12 months (G, H, and J). Atypical spindle-shaped cells are observed within the cortex in the Mcm4Chaos3/–Mcm3+/– adrenals 3.5 months (arrows in F), with a more severe phenotype at 12 months (H). The normal capsule architecture in the wild-type (I) is lost adjacent to the abnormal cells (J). (K–V) Atypical cells in the cortex are not steroidogenic. 3.5-month-old wild-type (K, Q, and S) and Mcm4Chaos3/–Mcm3+/– (L, R, and U) adrenals were stained for P450 SCC (K, L, M, and N), CYP11B1 (B1) (O), double SCC-B1 (P), and GATA-4 (Q and R). The atypical cells populating the zona fasciculata in Mcm4Chaos3/–Mcm3+/– adrenals are negative for both SCC and CYP11B1 (arrows in N and P). GATA-4 immunoreactivity was rarely observed in the wild-type adrenals and always in cells close to the capsule (arrows in Q). In Mcm4Chaos3/–Mcm3+/– samples, the atypical cells are GATA-4 positive (arrows in R). In situ hybridization on 12-month-old adrenals showed that Gli1 expression is restricted to the capsule in the wild-type (S) but detected in the cortex in the atypical cells in Mcm4Chaos3/–Mcm3+/– mice (U). T and V are sense probe controls. Cap, capsule; Med, medulla; ZF, zona fasciculata; ZG, zona glomerulosa. Scale bars: 100 μm (A–H, K–V), 40 μm (I and J).