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Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice
The respiratory rhythm is generated by the preBötzinger complex in the medulla oblongata, and is modulated by neurons in the retrotrapezoid nucleus (RTN), which are essential for accelerating respiration in response to high CO(2). Here we identify a LBX1 frameshift (LBX1(FS)) mutation in patients wi...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304989/ https://www.ncbi.nlm.nih.gov/pubmed/30487221 http://dx.doi.org/10.1073/pnas.1813520115 |
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author | Hernandez-Miranda, Luis Rodrigo Ibrahim, Daniel M. Ruffault, Pierre-Louis Larrosa, Madeleine Balueva, Kira Müller, Thomas de Weerd, Willemien Stolte-Dijkstra, Irene Hostra, Robert M. W. Brunet, Jean-François Fortin, Gilles Mundlos, Stefan Birchmeier, Carmen |
author_facet | Hernandez-Miranda, Luis Rodrigo Ibrahim, Daniel M. Ruffault, Pierre-Louis Larrosa, Madeleine Balueva, Kira Müller, Thomas de Weerd, Willemien Stolte-Dijkstra, Irene Hostra, Robert M. W. Brunet, Jean-François Fortin, Gilles Mundlos, Stefan Birchmeier, Carmen |
author_sort | Hernandez-Miranda, Luis Rodrigo |
collection | PubMed |
description | The respiratory rhythm is generated by the preBötzinger complex in the medulla oblongata, and is modulated by neurons in the retrotrapezoid nucleus (RTN), which are essential for accelerating respiration in response to high CO(2). Here we identify a LBX1 frameshift (LBX1(FS)) mutation in patients with congenital central hypoventilation. The mutation alters the C-terminal but not the DNA-binding domain of LBX1. Mice with the analogous mutation recapitulate the breathing deficits found in humans. Furthermore, the mutation only interferes with a small subset of Lbx1 functions, and in particular with development of RTN neurons that coexpress Lbx1 and Phox2b. Genome-wide analyses in a cell culture model show that Lbx1(FS) and wild-type Lbx1 proteins are mostly bound to similar sites, but that Lbx1(FS) is unable to cooperate with Phox2b. Thus, our analyses on Lbx1(FS) (dys)function reveals an unusual pathomechanism; that is, a mutation that selectively interferes with the ability of Lbx1 to cooperate with Phox2b, and thus impairs the development of a small subpopulation of neurons essential for respiratory control. |
format | Online Article Text |
id | pubmed-6304989 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-63049892018-12-28 Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice Hernandez-Miranda, Luis Rodrigo Ibrahim, Daniel M. Ruffault, Pierre-Louis Larrosa, Madeleine Balueva, Kira Müller, Thomas de Weerd, Willemien Stolte-Dijkstra, Irene Hostra, Robert M. W. Brunet, Jean-François Fortin, Gilles Mundlos, Stefan Birchmeier, Carmen Proc Natl Acad Sci U S A Biological Sciences The respiratory rhythm is generated by the preBötzinger complex in the medulla oblongata, and is modulated by neurons in the retrotrapezoid nucleus (RTN), which are essential for accelerating respiration in response to high CO(2). Here we identify a LBX1 frameshift (LBX1(FS)) mutation in patients with congenital central hypoventilation. The mutation alters the C-terminal but not the DNA-binding domain of LBX1. Mice with the analogous mutation recapitulate the breathing deficits found in humans. Furthermore, the mutation only interferes with a small subset of Lbx1 functions, and in particular with development of RTN neurons that coexpress Lbx1 and Phox2b. Genome-wide analyses in a cell culture model show that Lbx1(FS) and wild-type Lbx1 proteins are mostly bound to similar sites, but that Lbx1(FS) is unable to cooperate with Phox2b. Thus, our analyses on Lbx1(FS) (dys)function reveals an unusual pathomechanism; that is, a mutation that selectively interferes with the ability of Lbx1 to cooperate with Phox2b, and thus impairs the development of a small subpopulation of neurons essential for respiratory control. National Academy of Sciences 2018-12-18 2018-11-28 /pmc/articles/PMC6304989/ /pubmed/30487221 http://dx.doi.org/10.1073/pnas.1813520115 Text en Copyright © 2018 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) . |
spellingShingle | Biological Sciences Hernandez-Miranda, Luis Rodrigo Ibrahim, Daniel M. Ruffault, Pierre-Louis Larrosa, Madeleine Balueva, Kira Müller, Thomas de Weerd, Willemien Stolte-Dijkstra, Irene Hostra, Robert M. W. Brunet, Jean-François Fortin, Gilles Mundlos, Stefan Birchmeier, Carmen Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice |
title | Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice |
title_full | Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice |
title_fullStr | Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice |
title_full_unstemmed | Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice |
title_short | Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice |
title_sort | mutation in lbx1/lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6304989/ https://www.ncbi.nlm.nih.gov/pubmed/30487221 http://dx.doi.org/10.1073/pnas.1813520115 |
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