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

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Item Type:Article
Title:Mutation in LBX1/Lbx1 precludes transcription factor cooperativity and causes congenital hypoventilation in humans and mice
Creators Name:Hernandez-Miranda, L.R. and Ibrahim, D.M. and Ruffault, P.L. and Larrosa, M. and Balueva, K. and Müller, T. and de Weerd, W. and Stolte-Dijkstra, I. and Hostra, R.M.W. and Brunet, J.F. and Fortin, G. and Mundlos, S. and Birchmeier, C.
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 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.
Keywords:Congenital Hypoventilation, Transcriptional Cooperativity, LBX1/Lbx1, Phox2b, Neuronal Fate Change, Animals, Mice
Source:Proceedings of the National Academy of Sciences of the United States of America
ISSN:0027-8424
Publisher:National Academy of Sciences (U.S.A.)
Volume:115
Number:51
Page Range:13021-13026
Date:18 December 2018
Official Publication:https://doi.org/10.1073/pnas.1813520115
PubMed:View item in PubMed

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