Double NF1 inactivation affects adrenocortical function in NF1Prx1 mice and a human patient.
<h4>Background</h4>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...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-01-01
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| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0119030 |
| _version_ | 1830130932609187840 |
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| author | Karolina Kobus Daniela Hartl Claus Eric Ott Monika Osswald Angela Huebner Maja von der Hagen Denise Emmerich Jirko Kühnisch Hans Morreau Frederik J Hes Victor F Mautner Anja Harder Sigrid Tinschert Stefan Mundlos Mateusz Kolanczyk |
| author_facet | Karolina Kobus Daniela Hartl Claus Eric Ott Monika Osswald Angela Huebner Maja von der Hagen Denise Emmerich Jirko Kühnisch Hans Morreau Frederik J Hes Victor F Mautner Anja Harder Sigrid Tinschert Stefan Mundlos Mateusz Kolanczyk |
| author_sort | Karolina Kobus |
| collection | DOAJ |
| description | <h4>Background</h4>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.<h4>Materials and methods</h4>We analysed Nf1Prx1 mice and one case of adrenal cortical hyperplasia in a NF1patient.<h4>Results</h4>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.<h4>Conclusions</h4>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. |
| first_indexed | 2024-12-17T06:05:12Z |
| format | Article |
| id | doaj.art-e0dfcdbafa084e828677cdf02a011cd5 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-17T06:05:12Z |
| publishDate | 2015-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-e0dfcdbafa084e828677cdf02a011cd52022-12-21T22:00:45ZengPublic Library of Science (PLoS)PLoS ONE1932-62032015-01-01103e011903010.1371/journal.pone.0119030Double NF1 inactivation affects adrenocortical function in NF1Prx1 mice and a human patient.Karolina KobusDaniela HartlClaus Eric OttMonika OsswaldAngela HuebnerMaja von der HagenDenise EmmerichJirko KühnischHans MorreauFrederik J HesVictor F MautnerAnja HarderSigrid TinschertStefan MundlosMateusz Kolanczyk<h4>Background</h4>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.<h4>Materials and methods</h4>We analysed Nf1Prx1 mice and one case of adrenal cortical hyperplasia in a NF1patient.<h4>Results</h4>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.<h4>Conclusions</h4>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.https://doi.org/10.1371/journal.pone.0119030 |
| spellingShingle | Karolina Kobus Daniela Hartl Claus Eric Ott Monika Osswald Angela Huebner Maja von der Hagen Denise Emmerich Jirko Kühnisch Hans Morreau Frederik J Hes Victor F Mautner Anja Harder Sigrid Tinschert Stefan Mundlos Mateusz Kolanczyk Double NF1 inactivation affects adrenocortical function in NF1Prx1 mice and a human patient. PLoS ONE |
| title | Double NF1 inactivation affects adrenocortical function in NF1Prx1 mice and a human patient. |
| title_full | Double NF1 inactivation affects adrenocortical function in NF1Prx1 mice and a human patient. |
| title_fullStr | Double NF1 inactivation affects adrenocortical function in NF1Prx1 mice and a human patient. |
| title_full_unstemmed | Double NF1 inactivation affects adrenocortical function in NF1Prx1 mice and a human patient. |
| title_short | Double NF1 inactivation affects adrenocortical function in NF1Prx1 mice and a human patient. |
| title_sort | double nf1 inactivation affects adrenocortical function in nf1prx1 mice and a human patient |
| url | https://doi.org/10.1371/journal.pone.0119030 |
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