Adrenocortical dysplasia: a mouse model system for adrenocortical insufficiency

Abstract

A spontaneous autosomal recessive mutation causing disordered morphogenesis of the adrenal cortex has been identified in DW/J inbred strain mice and named adrenocortical dysplasia (acd). The acd mutant gene has been mapped just proximal to oligosyndactyly (Os) and esterase-1 (Es-1) in the central region of chromosome 8. Both male and female acd/acd mice are characterized by reduced survival, retarded growth, skin hyperpigmentation, poorly developed pelage and focal ureteral blockage leading to hydronephrosis. Morphometric measurements showed that acd/acd cortical cells and nuclei were increased sevenfold in volume; nuclei often showed a variety of inclusions. Cortical cells of acd/acd mice contained large numbers of mitochondria, smooth endoplasmic reticulum and lipid droplets characteristic of steroidogenic cells. While cortical X-zones failed to develop in acd/acd adrenals, medullary cells and nuclei were unaffected by mutant gene action. Resting serum corticosterone levels in female, but not male, mutant mice were significantly lower than in +/? normal littermates, whereas ACTH levels were significantly elevated in mutants of both sexes. Serum aldosterone levels were normal in acd/acd mice. Functional studies of adrenals cultured in vitro revealed that acd/acd adrenals secreted reduced amounts of corticosterone per pair of glands under both basal and ACTH-stimulated conditions. However, correction of the corticosterone secretion data to mg cortical mass in culture showed that the mutant cortical tissue secreted the same amount of glucocorticoid as did their +/? normal littermate glands. We conclude that the acd mutant gene acts in an unknown fashion to cause a fundamental defect in cellular proliferation in the adrenal cortex, leading to compensatory marked hypertrophy of cortical cells and grossly enlarged nuclei. The role of acd action in adrenal cortical development remains to be established.

Adrenocortical Growth and Cancer

“…De Martino et al reported in a cohort of 40 ACC several recurrent gains (chromosome 5, 7, 12, 19, and 20) and losses (1,22) (77). Recurrent amplification of CDK4 and deletion of CDKN2A (cyclin-dependent kinase inhibitor 2A) and CDKN2B (cyclin-dependent kinase inhibitor 2B) are also identified in this study.…”

“…The adrenocortical dysplasia gene Adrenocortical dysplasia (Acd) corresponds to a spontaneous autosomal recessive mouse mutant (22). The Acd mice show Acd and hypofunction.…”

Tpp1/Acd maintains genomic stability through a complex role in telomere protection

“…Through positional cloning we recently identified the genetic cause of a spontaneous mouse mutant known as the adrenocortical dysplasia mouse (acd) to be a splice donor site single-base substitution in the gene encoding the mouse homologue of TPP1 (Beamer et al 1994, Keegan et al 2005. This mouse gene was originally named Acd, but will be referred to hereafter as Tpp1/Acd.…”

Shwachman-Diamond Syndrome Protein SBDS Maintains Human Telomeres by Regulating Telomerase Recruitment

“…For example, several studies have suggested that TPP1 deficiency would completely block telomerase binding to telomeres, which in turn results in telomere attrition (Bisht et al, 2016; Nandakumar et al, 2012; Nandakumar and Cech, 2013; Xin et al, 2007). The ACD mouse, a spontaneously occurring mutant, contains a hypomorphic mutation in the mouse TPP1 gene ( Acd ), and it displays telomere dysfunction and a myriad of disease phenotypes, such as adrenal abnormality, heavy pigmentation, and reduced viability (Beamer et al, 1994; Keegan et al, 2005). Recently, mutations of TPP1 have also been found in patients with Hoyeraal-Hreidarsson syndrome, a telomere dysfunction disease that is a variant of dyskeratosis congenita (DC) (Glousker et al, 2015; Kocak et al, 2014).…”