Developmental Biology and Signal Transduction Group, Max-Delbrueck-Centrum in the Helmholtz Association, 13125 Berlin, Germany.
Development and Disease Group, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
Proc Natl Acad Sci U S A. 2018 Dec 18;115(51):13021-13026. doi: 10.1073/pnas.1813520115. Epub 2018 Nov 28.
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 Here we identify a frameshift ( ) mutation in patients with congenital central hypoventilation. The mutation alters the C-terminal but not the DNA-binding domain of 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 and wild-type Lbx1 proteins are mostly bound to similar sites, but that Lbx1 is unable to cooperate with Phox2b. Thus, our analyses on Lbx1 (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.
呼吸节律由延髓中的 Pre-Bötzinger 复合体产生，并受位于脑桥被盖腹外侧部（RTN）的神经元调节，这些神经元对于加速呼吸以响应高 CO2 至关重要。在这里，我们在先天性中枢性通气不足的患者中鉴定出一个 frameshift（移码）突变。该突变改变了 Lbx1 的 C 末端但不改变其 DNA 结合结构域。具有类似突变的小鼠重现了人类发现的呼吸缺陷。此外，该突变仅干扰 Lbx1 功能的一小部分，特别是干扰共表达 Lbx1 和 Phox2b 的 RTN 神经元的发育。在细胞培养模型中的全基因组分析表明，Lbx1 和野生型 Lbx1 蛋白主要与相似的位点结合，但 Lbx1 无法与 Phox2b 合作。因此，我们对 Lbx1（功能障碍）的分析揭示了一种不寻常的发病机制；即，一种选择性干扰 Lbx1 与 Phox2b 合作能力的突变，从而损害了呼吸控制所必需的一小部分神经元的发育。
