Double NF1 inactivation affects adrenocortical function in NF1Prx1 mice and a human patient

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Karolina Kobus - , Charité – Universitätsmedizin Berlin, Max Planck Institut für Molekulare Genetik (Autor:in)
  • Daniela Hartl - , Charité – Universitätsmedizin Berlin (Autor:in)
  • Claus Eric Ott - , Max Planck Institut für Molekulare Genetik (Autor:in)
  • Monika Osswald - , Max Planck Institut für Molekulare Genetik (Autor:in)
  • Angela Huebner - , Klinik und Poliklinik für Kinder- und Jugendmedizin (Autor:in)
  • Maja Von Der Hagen - , Klinik und Poliklinik für Kinder- und Jugendmedizin, Abteilung für Neuropädiatrie (Autor:in)
  • Denise Emmerich - , Max Planck Institut für Molekulare Genetik (Autor:in)
  • Jirko Kühnisch - , Charité – Universitätsmedizin Berlin, Max Planck Institut für Molekulare Genetik (Autor:in)
  • Hans Morreau - , Leiden University (Autor:in)
  • Frederik J. Hes - , Leiden University (Autor:in)
  • Victor F. Mautner - , Universität Hamburg (Autor:in)
  • Anja Harder - , Westfälische Wilhelms-Universität Münster (Autor:in)
  • Sigrid Tinschert - , Medizinische Universität Innsbruck (Autor:in)
  • Stefan Mundlos - , Charité – Universitätsmedizin Berlin, Max Planck Institut für Molekulare Genetik, Berliner Institut für Gesundheitsforschung in der Charité (Autor:in)
  • Mateusz Kolanczyk - , Charité – Universitätsmedizin Berlin, Max Planck Institut für Molekulare Genetik (Autor:in)

Abstract

Background: Neurofibromatosis 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 Methods: We analysed Nf1Prx1 mice and one case of adrenal cortical hyperplasia in a NF1patient. Results: In 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. Conclusions: Our 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.

Details

OriginalspracheEnglisch
Aufsatznummere0119030
FachzeitschriftPLoS ONE
Jahrgang10
Ausgabenummer3
PublikationsstatusVeröffentlicht - 16 März 2015
Peer-Review-StatusJa

Externe IDs

Scopus 84925014350
PubMed 25775093