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  Mutation in <em>LBX1/Lbx1</em> precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice

Hernandez-Miranda, L. R., Ibrahim, D., Ruffault, P.-L., Larrosa, M., Balueva, K., Müller, T., et al. (2018). Mutation in <em>LBX1/Lbx1</em> precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice. Proceedings of the National Academy of Sciences of the United States of America, 115(51), 13021-13026. doi:10.1073/pnas.1813520115.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-5A62-A Version Permalink: http://hdl.handle.net/21.11116/0000-0003-5A63-9
Genre: Journal Article

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© 2018 the Author(s). Published by PNAS

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 Creators:
Hernandez-Miranda, Luis Rodrigo, Author
Ibrahim, Daniel1, Author              
Ruffault, Pierre-Louis, Author
Larrosa, Madeleine, Author
Balueva, Kira, Author
Müller, Thomas, Author
Weerd, Willemien de, Author
Stolte-Dijkstra, Irene, Author
Hostra, Robert M. W., Author
Brunet, Jean-François, Author
Fortin, Gilles, Author
Mundlos, Stefan1, Author              
Birchmeier, Carmen, Author
Affiliations:
1Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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 Abstract: Maintaining low CO2 levels in our bodies is critical for life and depends on neurons that generate the respiratory rhythm and monitor tissue gas levels. Inadequate response to increasing levels of CO2 is common in congenital hypoventilation diseases. Here, we identified a mutation in LBX1, a homeodomain transcription factor, that causes congenital hypoventilation in humans. The mutation alters the C terminus of the protein without disturbing its DNA-binding domain. Mouse models carrying an analogous mutation recapitulate the disease. The mutation spares most Lbx1 functions, but selectively affects development of a small group of neurons central in respiration. Our work reveals a very unusual pathomechanism, a mutation that hampers a small subset of functions carried out by a transcription factor.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 CO2. Here we identify a LBX1 frameshift (LBX1FS) 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 Lbx1FS and wild-type Lbx1 proteins are mostly bound to similar sites, but that Lbx1FS is unable to cooperate with Phox2b. Thus, our analyses on Lbx1FS (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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Language(s): eng - English
 Dates: 2018-11-282018-12-18
 Publication Status: Published in print
 Pages: -
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 Identifiers: DOI: 10.1073/pnas.1813520115
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Title: Proceedings of the National Academy of Sciences of the United States of America
  Other : Proc. Acad. Sci. USA
  Other : Proc. Acad. Sci. U.S.A.
  Other : Proceedings of the National Academy of Sciences of the USA
  Abbreviation : PNAS
Source Genre: Journal
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Publ. Info: Washington, D.C. : National Academy of Sciences
Pages: - Volume / Issue: 115 (51) Sequence Number: - Start / End Page: 13021 - 13026 Identifier: ISSN: 0027-8424
CoNE: https://pure.mpg.de/cone/journals/resource/954925427230