title: Double NF1 inactivation affects adrenocortical function in NF1Prx1 mice and a human patient.
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.
  
  
  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.
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité, Universitätsmedizin Berlin, Berlin, Germany; Max Planck Institute for Molecular Genetics, FG Development & Disease, Berlin, Germany.
authors.forename: Karolina
authors.initials: K
authors.lastname: Kobus
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité, Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Hartl
authors.affiliation: Max Planck Institute for Molecular Genetics, FG Development & Disease, Berlin, Germany.
authors.forename: Claus Eric
authors.initials: CE
authors.lastname: Ott
authors.affiliation: Max Planck Institute for Molecular Genetics, FG Development & Disease, Berlin, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Osswald
authors.affiliation: Klinik für Kinder- und Jugendmedizin, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Huebner
authors.affiliation: Abteilung Neuropädiatrie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: von der Hagen
authors.affiliation: Max Planck Institute for Molecular Genetics, FG Development & Disease, Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Emmerich
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité, Universitätsmedizin Berlin, Berlin, Germany; Max Planck Institute for Molecular Genetics, FG Development & Disease, Berlin, Germany.
authors.forename: Jirko
authors.initials: J
authors.lastname: Kühnisch
authors.affiliation: Department of Pathology, Leiden University Center, Albinusdreef 2, 2333ZA, Leiden, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.affiliation: Department of Clinical Genetics, Leiden University Center, Albinusdreef 2, 2333ZA, Leiden, The Netherlands.
authors.forename: Frederik J
authors.initials: FJ
authors.lastname: Hes
authors.affiliation: Department of Maxillofacial Surgery, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: Victor F
authors.initials: VF
authors.lastname: Mautner
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Harder
authors.affiliation: Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Tinschert
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité, Universitätsmedizin Berlin, Berlin, Germany; Max Planck Institute for Molecular Genetics, FG Development & Disease, Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.affiliation: Institute for Medical Genetics and Human Genetics, Charité, Universitätsmedizin Berlin, Berlin, Germany; Max Planck Institute for Molecular Genetics, FG Development & Disease, Berlin, Germany.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Kolanczyk
mesh_terms: D000293:Adolescent; D000302:Adrenal Cortex / Q000378:metabolism / Q000473:pathology*; D000312:Adrenal Hyperplasia, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000818:Animals; D002648:Child; D002675:Child, Preschool; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D051379:Mice; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000378:metabolism; D025542:Neurofibromin 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D025542:Neurofibromin 1; C489936:Prrx1 protein, mouse; D000324:Adrenocorticotropic Hormone