English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

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

Kobus, K., Hartl, D., Ott, C. E., Osswald, M., Huebner, A., von der Hagen, M., et al. (2015). Double NF1 inactivation affects adrenocortical function in NF1Prx1 mice and a human patient. PLoS One, 10(3): e0119030. doi:10.1371/journal.pone.0119030.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-6105-1 Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-6106-0
Genre: Journal Article

Files

show Files
hide Files
:
Kobus.PDF (Publisher version), 2MB
Name:
Kobus.PDF
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
© 2015 Kobus et al

Locators

show
hide
Description:
-

Creators

show
hide
 Creators:
Kobus, K., Author
Hartl, D., Author
Ott, C. E., Author
Osswald, M.1, Author              
Huebner, A., Author
von der Hagen, M., Author
Emmerich, D.1, Author
Kühnisch, J., Author
Morreau, H., Author
Hes, F. J., Author
Mautner, V. F., Author
Harder, A., Author
Tinschert, S., Author
Mundlos, S.1, 2, 3, Author              
Kolanczyk, M., Author
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              
2Institute for Medical Genetics and Human Genetics, Charité, Universitätsmedizin Berlin, Berlin, ou_persistent22              
3Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany, ou_persistent22              

Content

show
hide
Free keywords: Adolescent Adrenal Cortex/metabolism/*pathology Adrenal Hyperplasia, Congenital/*genetics/metabolism/pathology Adrenocorticotropic Hormone/metabolism Animals Child Child, Preschool Female Homeodomain Proteins/*genetics Humans Loss of Heterozygosity Mice Neurofibromatosis 1/*genetics/metabolism Neurofibromin 1/*genetics/metabolism
 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

show
hide
Language(s): eng - English
 Dates: 2015-03-16
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: -
 Identifiers: DOI: 10.1371/journal.pone.0119030
ISSN: 1932-6203 (Electronic)
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: PLoS One
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: San Francisco, CA : Public Library of Science
Pages: - Volume / Issue: 10 (3) Sequence Number: e0119030 Start / End Page: - Identifier: ISSN: 1932-6203
CoNE: /journals/resource/1000000000277850