Endocrine Abstracts (2011) 27 OC2.3

MCM4 mutation causes a novel DNA replication disorder associated with short stature and adrenal failure

Claire Hughes1, Leonardo Guasti1, Eirini Meimaridou1, Chen-Hua Chaung2, John Schimenti2, Peter King1, Colm Costigan3, Adrian Clark1 & Louise Metherell1

1Barts and the London School of Medicine and Dentistry, QMUL, London, UK; 2College of Veterinary Medicine, Cornell University, New York, New York, USA; 3Our Lady’s Children’s Hospital, Dublin, Ireland.

Introduction: A unique variant of familial glucocorticoid deficiency (FGD) exists in the Irish travelling community, a genetically isolated population with high levels of consanguinity. Affected children develop hypocortisolaemia and raised ACTH but retain normal renin and aldosterone levels. Children also have short stature, evidence of increased chromosomal breakage and natural killer cell deficiency.

Methods: We sought areas of homozygosity common to affected patients and subsequently interrogated these areas using massively parallel sequencing.

Results: Targeted exome sequencing identified a variant (c.71-1insG) in mini chromosome maintenance-deficient 4 homologue (MCM4) that is predicted to result in a severely truncated protein (p.Pro24ArgfsX4). Western blotting in patients revealed the abolition of the major 96 kDa isoform, however a minor 85 kDa isoform was preserved. An MCM4 depletion mouse model has grossly abnormal adrenal morphology, with the steroidogenic cortex being infiltrated by GATA4 positive cells significantly reducing the number of steroidogenic cells in the zona fasciculata.

Conclusion: MCM4 is essential for normal DNA replication and genome stability in all eukaryotes. We have identified a mutation in MCM4 characterising a novel disorder of DNA replication that includes growth retardation, increased chromosomal fragility and variable immune deficiency. In addition this disorder includes adrenal insufficiency and we have shown in mutant mouse adrenals that this can be explained by replacement of steroidogenic cells with non-steroidogenic ones reducing the capacity of the adrenal to produce glucocorticoid. This seemingly specific impact on adrenal function may reflect a defect in adrenal stem cell differentiation.