2. Academic Validation
  3. Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice

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

  • Proc Natl Acad Sci U S A. 2018 Dec 18;115(51):13021-13026. doi: 10.1073/pnas.1813520115.
Luis Rodrigo Hernandez-Miranda 1,  Daniel M Ibrahim 2 3,  Pierre-Louis Ruffault 1 4,  Madeleine Larrosa 1,  Kira Balueva 1,  Thomas Müller 1,  Willemien de Weerd 5,  Irene Stolte-Dijkstra 6,  Robert M W Hostra 6,  Jean-François Brunet 7,  Gilles Fortin 4,  Stefan Mundlos 2 3,  Carmen Birchmeier 8
Affiliations

Affiliations

  • 1 Developmental Biology and Signal Transduction Group, Max-Delbrueck-Centrum in the Helmholtz Association, 13125 Berlin, Germany.
  • 2 Development and Disease Group, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
  • 3 Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, 13353 Berlin, Germany.
  • 4 Hindbrain Integrative Neurobiology Group, Paris-Saclay Institute for Neuroscience, UMR9197/CNRS, 91190 Gif sur Yvette, France.
  • 5 Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
  • 6 Department of Clinical Genetics, Erasmus University Medical Center, 3015 CN Rotterdam, The Netherlands.
  • 7 Institut de Biologie, École Normale Supérieure, 75005 Paris, France.
  • 8 Developmental Biology and Signal Transduction Group, Max-Delbrueck-Centrum in the Helmholtz Association, 13125 Berlin, Germany; [email protected].
PMID: 30487221 DOI: 10.1073/pnas.1813520115
Abstract

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.

Keywords

LBX1/Lbx1; Phox2b; congenital hypoventilation; neuronal fate change; transcriptional cooperativity.

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