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

Hernández-Miranda, Luis R.; Ibrahim, Daniel M.; Ruffault, Pierre-Louis; Larrosa, Madeleine; Balueva, Kira; Müller, Thomas; Weerd, Willemien de; Stolte‐Dijkstra, Irene; Hostra, Robert M W; Brunet, Jean‐François; Fortin, Gilles; Mundlos, Stefan; Birchmeier, Carmen

doi:10.1073/pnas.1813520115

Cited by 31 publications

(81 citation statements)

References 32 publications

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“…Yet, inducing Lbx1 FS in the full dB2 domain (using Phox2b ) phenocopied all aspects of the full body Lbx1 FS mice. This shows that a yet to be defined population in the dorsal dB2 domain contributes to respiratory control and is necessary for neonatal survival in absence of RTN/pF neurons (Hernandez‐Miranda et al, ).…”

Section: Dorsal‐ventral Patterning Genes Guiding Respiratory Circuit mentioning

confidence: 99%

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Development of the brainstem respiratory circuit

Heijden

Zoghbi

2019

WIREs Developmental Biology

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The respiratory circuit is comprised of over a dozen functionally and anatomically segregated brainstem nuclei that work together to control respiratory rhythms. These respiratory rhythms emerge prenatally but only acquire vital importance at birth, which is the first time the respiratory circuit faces the sole responsibility for O2/CO2 homeostasis. Hence, the respiratory circuit has little room for trial‐and‐error‐dependent fine tuning and relies on a detailed genetic blueprint for development. This blueprint is provided by transcription factors that have specific spatiotemporal expression patterns along the rostral‐caudal or dorsal‐ventral axis of the developing brainstem, in proliferating precursor cells and postmitotic neurons. Studying these transcription factors in mice has provided key insights into the functional segregation of respiratory control and the vital importance of specific respiratory nuclei. Many studies converge on just two respiratory nuclei that each have rhythmogenic properties during the prenatal period: the preBötzinger complex (preBötC) and retrotrapezoid nucleus/parafacial nucleus (RTN/pF). Here, we discuss the transcriptional regulation that guides the development of these nuclei. We also summarize evidence showing that normal preBötC development is necessary for neonatal survival, and that neither the preBötC nor the RTN/pF alone is sufficient to sustain normal postnatal respiratory rhythms. Last, we highlight several studies that use intersectional genetics to assess the necessity of transcription factors only in subregions of their expression domain. These studies independently demonstrate that lack of RTN/pF neurons weakens the respiratory circuit, yet these neurons are not necessary for neonatal survival because developmentally related populations can compensate for abnormal RTN/pF function at birth. This article is categorized under: Nervous System Development > Vertebrates: Regional Development

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Section: Dorsal‐ventral Patterning Genes Guiding Respiratory Circuit mentioning

confidence: 99%

“…Therefore, silencing FBMs in relatively anoxic conditions might be a way to preserve oxygen for other energy-demanding processes. domain contributes to respiratory control and is necessary for neonatal survival in absence of RTN/pF neurons (Hernandez-Miranda et al, 2018).…”

Section: Lbx1 Defines All Db Interneuronsmentioning

confidence: 99%

Development of the brainstem respiratory circuit

Heijden

Zoghbi

2019

WIREs Developmental Biology

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“…Normal values of blood gases vary with age and methods used. Arterial partial pressure of carbon dioxide (PaCO 2 ) between 4.7-6.0 kPa (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45) and arterial oxygen saturation (SaO 2 ) ≥ 95% are considered as normal (Table 1).…”

Section: Definition Of Alveolar Hypoventilationmentioning

confidence: 99%

“…Recently, mutations of two new genes, MYO1H and LBX1, have been found in two consanguineous families with CCHS [39,88]. However, there are yet unknown genes that affect the development of neurons responsible for breathing control.…”

Section: Do the Phox2b Anomalies Predict The Clinical Presentation?mentioning

confidence: 99%

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Guidelines for diagnosis and management of congenital central hypoventilation syndrome

Trang

Samuels

Ceccherini

et al. 2020

Orphanet J Rare Dis

137

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Background Congenital Central Hypoventilation Syndrome (CCHS) is a rare condition characterized by an alveolar hypoventilation due to a deficient autonomic central control of ventilation and a global autonomic dysfunction. Paired-like homeobox 2B (PHOX2B) mutations are found in most of the patients with CCHS. In recent years, the condition has evolved from a life-threatening neonatal onset disorder to include broader and milder clinical presentations, affecting children, adults and families. Genes other than PHOX2B have been found responsible for CCHS in rare cases and there are as yet other unknown genes that may account for the disease. At present, management relies on lifelong ventilatory support and close follow up of dysautonomic progression. Body This paper provides a state-of-the-art comprehensive description of CCHS and of the components of diagnostic evaluation and multi-disciplinary management, as well as considerations for future research. Conclusion Awareness and knowledge of the diagnosis and management of this rare disease should be brought to a large health community including adult physicians and health carers.

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Congenital central hypoventilation syndrome in Chinese population: Analysis of three new cases and review of the literature

Wang,

Chen

et al. 2023

Molec Gen & Gen Med

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BackgroundCongenital central hypoventilation syndrome (CCHS) is a rare autosomal dominant disease that is mainly caused by PHOX2B mutations. The purpose of this study is to analyze and summarize the clinical and genetic characteristics of CCHS patients in the Chinese population from our study and previous literature.MethodsThe potential pathogenic gene mutations of CCHS were identified and verified by next generation sequencing combined with Sanger sequencing, fluorescent probe PCR and capillary electrophoresis. The clinical characteristics and gene mutations of CCHS cases in Chinese population were summarized from our study and previous literature to explore the genotype–phenotype correlations.ResultsWe identified 48 CCHS cases including three new cases from our report in China. Overall, 77.1% of the patients had PHOX2B polyalanine repeat expansion mutations (PARMs), and the remaining 22.9% had 10 distinct PHOX2B non‐polyalanine repeat expansion mutations (NPARMs). Compared to those with PARMs, patients with NPARMs were more likely to have premature birth (54.5% vs. 2.8%, p < 0.001) and lower birth weight (33.3% vs. 3.2%, p = 0.030), with statistical significance. The patients with PARMs were more likely to have cardiovascular defects (64.9% vs. 27.3%, p = 0.063), cerebral hemorrhage (29.7% vs. 9.1%, p = 0.322) and seizures (37.8% vs. 9.1%, p = 0.151) than those with NPARMs, with no statistical significance.ConclusionsCCHS patients with PHOX2B NPARMs were more likely to have premature birth and low birth weight, while PHOX2B PARMs tended to be positively associated with the risk of cardiovascular defects, cerebral hemorrhage and seizures in Chinese population.

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

Cited by 31 publications

References 32 publications

Development of the brainstem respiratory circuit

Development of the brainstem respiratory circuit

Guidelines for diagnosis and management of congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome in Chinese population: Analysis of three new cases and review of the literature

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