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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2018
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.
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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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