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Relevance of polymorphisms in MC4R and BDNF in short normal stature

BACKGROUND: Variation in genes of the leptinergic-melanocortinergic system influence both body weight and height. Because short normal stature (SNS) is characterized by reduced body height, delayed maturation and leanness, allelic variation of genes in this pathway are hypothesized to affect this co...

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Autores principales: Herrfurth, Nikolas, Volckmar, Anna-Lena, Peters, Triinu, Kleinau, Gunnar, Müller, Anne, Cetindag, Cigdem, Schonnop, Laura, Föcker, Manuel, Dempfle, Astrid, Wudy, Stefan A., Grant, Struan F. A., Reinehr, Thomas, Cousminer, Diana L., Hebebrand, Johannes, Biebermann, Heike, Hinney, Anke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106737/
https://www.ncbi.nlm.nih.gov/pubmed/30134862
http://dx.doi.org/10.1186/s12887-018-1245-1
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author Herrfurth, Nikolas
Volckmar, Anna-Lena
Peters, Triinu
Kleinau, Gunnar
Müller, Anne
Cetindag, Cigdem
Schonnop, Laura
Föcker, Manuel
Dempfle, Astrid
Wudy, Stefan A.
Grant, Struan F. A.
Reinehr, Thomas
Cousminer, Diana L.
Hebebrand, Johannes
Biebermann, Heike
Hinney, Anke
author_facet Herrfurth, Nikolas
Volckmar, Anna-Lena
Peters, Triinu
Kleinau, Gunnar
Müller, Anne
Cetindag, Cigdem
Schonnop, Laura
Föcker, Manuel
Dempfle, Astrid
Wudy, Stefan A.
Grant, Struan F. A.
Reinehr, Thomas
Cousminer, Diana L.
Hebebrand, Johannes
Biebermann, Heike
Hinney, Anke
author_sort Herrfurth, Nikolas
collection PubMed
description BACKGROUND: Variation in genes of the leptinergic-melanocortinergic system influence both body weight and height. Because short normal stature (SNS) is characterized by reduced body height, delayed maturation and leanness, allelic variation of genes in this pathway are hypothesized to affect this common condition. METHODS: We analyzed the coding regions of LEP, MC4R, MRAP2 and BDNF in 185 children with SNS (height < 5th percentile) to search for non-synonymous and frameshift variants. For association studies (two-sided χ(2)-tests) population-based data sets (ExAC, EVS and KORA) were used. Cyclic AMP accumulation, cell surface expression, central expression and MAP kinase activation were assayed in vitro to determine the functional implications of identified variants. RESULTS: We detected eleven variants predicted to be protein-altering, four in MC4R, four in BDNF, and three in MRAP2. No variants were found in LEP. In vitro analysis implied reduced function for the MC4R variant p.Met215Ile. Loss-of-function is contrary to expectations based on obesity studies, and thus does not support that this variant is relevant for SNS. The minor SNP alleles at MC4R p.Val103Ile and BDNF p.Val66Met were nominally associated with SNS. CONCLUSION: Taken together, although genes of the leptinergic-melanocortinergic system are important for normal growth, our data do not support the involvement of rare mutations in LEP, MC4R, MRAP2 or BDNF in short normal stature. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12887-018-1245-1) contains supplementary material, which is available to authorized users.
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spelling pubmed-61067372018-08-29 Relevance of polymorphisms in MC4R and BDNF in short normal stature Herrfurth, Nikolas Volckmar, Anna-Lena Peters, Triinu Kleinau, Gunnar Müller, Anne Cetindag, Cigdem Schonnop, Laura Föcker, Manuel Dempfle, Astrid Wudy, Stefan A. Grant, Struan F. A. Reinehr, Thomas Cousminer, Diana L. Hebebrand, Johannes Biebermann, Heike Hinney, Anke BMC Pediatr Research Article BACKGROUND: Variation in genes of the leptinergic-melanocortinergic system influence both body weight and height. Because short normal stature (SNS) is characterized by reduced body height, delayed maturation and leanness, allelic variation of genes in this pathway are hypothesized to affect this common condition. METHODS: We analyzed the coding regions of LEP, MC4R, MRAP2 and BDNF in 185 children with SNS (height < 5th percentile) to search for non-synonymous and frameshift variants. For association studies (two-sided χ(2)-tests) population-based data sets (ExAC, EVS and KORA) were used. Cyclic AMP accumulation, cell surface expression, central expression and MAP kinase activation were assayed in vitro to determine the functional implications of identified variants. RESULTS: We detected eleven variants predicted to be protein-altering, four in MC4R, four in BDNF, and three in MRAP2. No variants were found in LEP. In vitro analysis implied reduced function for the MC4R variant p.Met215Ile. Loss-of-function is contrary to expectations based on obesity studies, and thus does not support that this variant is relevant for SNS. The minor SNP alleles at MC4R p.Val103Ile and BDNF p.Val66Met were nominally associated with SNS. CONCLUSION: Taken together, although genes of the leptinergic-melanocortinergic system are important for normal growth, our data do not support the involvement of rare mutations in LEP, MC4R, MRAP2 or BDNF in short normal stature. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12887-018-1245-1) contains supplementary material, which is available to authorized users. BioMed Central 2018-08-22 /pmc/articles/PMC6106737/ /pubmed/30134862 http://dx.doi.org/10.1186/s12887-018-1245-1 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Herrfurth, Nikolas
Volckmar, Anna-Lena
Peters, Triinu
Kleinau, Gunnar
Müller, Anne
Cetindag, Cigdem
Schonnop, Laura
Föcker, Manuel
Dempfle, Astrid
Wudy, Stefan A.
Grant, Struan F. A.
Reinehr, Thomas
Cousminer, Diana L.
Hebebrand, Johannes
Biebermann, Heike
Hinney, Anke
Relevance of polymorphisms in MC4R and BDNF in short normal stature
title Relevance of polymorphisms in MC4R and BDNF in short normal stature
title_full Relevance of polymorphisms in MC4R and BDNF in short normal stature
title_fullStr Relevance of polymorphisms in MC4R and BDNF in short normal stature
title_full_unstemmed Relevance of polymorphisms in MC4R and BDNF in short normal stature
title_short Relevance of polymorphisms in MC4R and BDNF in short normal stature
title_sort relevance of polymorphisms in mc4r and bdnf in short normal stature
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106737/
https://www.ncbi.nlm.nih.gov/pubmed/30134862
http://dx.doi.org/10.1186/s12887-018-1245-1
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