Double NF1 Inactivation Affects Adrenocortical Function in NF1Prx1 Mice and a Human Patient

Abstract

BackgroundNeurofibromatosis type I (NF1, MIM#162200) is a relatively frequent genetic condition, which predisposes to tumor formation. Apart from tumors, individuals with NF1 often exhibit endocrine abnormalities such as precocious puberty (2,5–5% of NF1 patients) and some cases of hypertension (16% of NF1 patients). Several cases of adrenal cortex adenomas have been described in NF1 individuals supporting the notion that neurofibromin might play a role in adrenal cortex homeostasis. However, no experimental data were available to prove this hypothesis.Materials and MethodsWe analysed Nf1Prx1 mice and one case of adrenal cortical hyperplasia in a NF1patient.ResultsIn Nf1Prx1 mice Nf1 is inactivated in the developing limbs, head mesenchyme as well as in the adrenal gland cortex, but not the adrenal medulla or brain. We show that adrenal gland size is increased in NF1Prx1 mice. Nf1Prx1 female mice showed corticosterone and aldosterone overproduction. Molecular analysis of Nf1 deficient adrenals revealed deregulation of multiple proteins, including steroidogenic acute regulatory protein (StAR), a vital mitochondrial factor promoting transfer of cholesterol into steroid making mitochondria. This was associated with a marked upregulation of MAPK pathway and a female specific increase of cAMP concentration in murine adrenal lysates. Complementarily, we characterized a patient with neurofibromatosis type I with macronodular adrenal hyperplasia with ACTH-independent cortisol overproduction. Comparison of normal control tissue- and adrenal hyperplasia- derived genomic DNA revealed loss of heterozygosity (LOH) of the wild type NF1 allele, showing that biallelic NF1 gene inactivation occurred in the hyperplastic adrenal gland.ConclusionsOur data suggest that biallelic loss of Nf1 induces autonomous adrenal hyper-activity. We conclude that Nf1 is involved in the regulation of adrenal cortex function in mice and humans.

Gene-Level Regulation of Acupuncture Therapy in Spontaneously Hypertensive Rats: A Whole Transcriptome Analysis

“…It is well known that Nf1 mutations lead to a common autosomal dominant disorder, neurofibromatosis type 1. The neurofibromatosis type 1 patients have an increased incidence of cardiovascular diseases, including obstructive vascular disorders and hypertension [31]. The gamma-aminobutyric acid B-type receptor unit 2 (Gabbr1) expressed in paraventricular nucleus (PVN) is important in controlling sympathetic activity, and its upregulation attenuated sympathoexcitation in chronic heart failure [32, 33].…”

Adrenal cortical hyperplasia: diagnostic workup, subtypes, imaging features and mimics

“…7 Subclinical brain white matter involvement in CAH is seen as multiple T 2 hyperintense white matter foci, and may be due to hormonal imbalance during brain development or to corticosteroid treatments. 25 Bergamachi et al found a suggestion of association of CAH with demyelinating diseases. 25 Mimics of adrenal cortical hyperplasia Several abnormalities may result in diffuse adrenal enlargement, with apparent maintenance of adreniform shape.…”

“…25 Bergamachi et al found a suggestion of association of CAH with demyelinating diseases. 25 Mimics of adrenal cortical hyperplasia Several abnormalities may result in diffuse adrenal enlargement, with apparent maintenance of adreniform shape. These mimics can resemble cortical hyperplasia.…”

Attention deficit hyperactivity disorder (ADHD) in phenotypically similar neurogenetic conditions: Turner syndrome and the RASopathies

“…Brain and behavioural phenotypes in NF1 patients may also be influenced by altered levels of circulating glucocorticoids. It has recently been shown that deletion of the NF1 gene in the adrenal cortex increases circulating levels of stress hormones (corticosterone/cortisol) in mouse models and patients [ 92 ]. In individuals with ADHD alone, basal cortisol levels tend to be equivalent to those seen in non-affected individuals [ 93 ] and therefore increased basal stress hormone levels are unlikely to explain the increased propensity to ADHD in NF1.…”