ArticleThe Journal of biological chemistry2016
Alanine Expansions Associated with Congenital Central Hypoventilation Syndrome Impair PHOX2B Homeodomain-mediated Dimerization and Nuclear Import.
Article in The Journal of biological chemistry, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 29 citations in OpenAlex.
- PHOX2B defects alter protein folding, cell-cycle, and mitochondrial pathways in an in vitro model of CCHS.Molecular medicine (Cambridge, Mass.) · 2026Article
- PHOX2B deletion in congenital central hypoventilation syndrome: is this sufficient for pathogenesis?Journal of human genetics · 2026Article
- Recognition of a Critical Functional Domain and ImprovedHuman mutation · 2026Article
- CRISPR/Cas9-mediatedFrontiers in physiology · 2026Article
- Structural characterization of PHOX2B and its DNA interaction shed light on the molecular basis of the +7Ala variant pathogenicity in CCHS.Chemical science · 2024Article
- Article
- Etonogestrel Administration Reduces the Expression of PHOX2B and Its Target Genes in the Solitary Tract Nucleus.International journal of molecular sciences · 2022Article
- Non-polyalanine repeat mutation in PHOX2B is detected in autopsy cases of sudden unexpected infant death.PloS one · 2022Article
- Paired-like homeobox gene (PHOX2B) nonpolyalanine repeat expansion mutations (NPARMs): genotype-phenotype correlation in congenital central hypoventilation syndrome (CCHS).Genetics in medicine : official journal of the American College of Medical Genetics · 2021Article
- Reduced PHOX2B stability causes axonal growth impairment in motor neurons with TARDBP mutations.Stem cell reports · 2021Article
- Research Advances on Therapeutic Approaches to Congenital Central Hypoventilation Syndrome (CCHS).Frontiers in neuroscience · 2020Review
- A Novel c.676_677insGJournal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine · 2019Article
- Expanding the phenotype of congenital central hypoventilation syndrome impacts management decisions.American journal of medical genetics. Part A · 2018Article
- Structural and functional differences in PHOX2B frameshift mutations underlie isolated or syndromic congenital central hypoventilation syndrome.Human mutation · 2018Article
- Intrinsic Disorder in Proteins with Pathogenic Repeat Expansions.Molecules (Basel, Switzerland) · 2017Review
- Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome.American journal of medical genetics. Part A · 2017Article
- Expanded polyalanine tracts function as nuclear export signals and promote protein mislocalization via eEF1A1 factor.The Journal of biological chemistry · 2017Article
- Congenital central hypoventilation syndrome: a bedside-to-bench success story for advancing early diagnosis and treatment and improved survival and quality of life.Pediatric research · 2017Review
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Heterozygous mutations of the human PHOX2B gene, a key regulator of autonomic nervous system development, lead to congenital central hypoventilation syndrome (CCHS), a neurodevelopmental disorder characterized by a failure in the autonomic control of breathing. Polyalanine expansions in the 20-residues region of the C terminus of PHOX2B are the major mutations responsible for CCHS. Elongation of the alanine stretch in PHOX2B leads to a protein with altered DNA binding, transcriptional activity, and nuclear localization and the possible formation of cytoplasmic aggregates; furthermore, the findings of various studies support the idea that CCHS is not due to a pure loss of function mechanism but also involves a dominant negative effect and/or toxic gain of function for PHOX2B mutations. Because PHOX2B forms homodimers and heterodimers with its paralogue PHOX2A in vitro, we tested the hypothesis that the dominant negative effects of the mutated proteins are due to non-functional interactions with the wild-type protein or PHOX2A using a co-immunoprecipitation assay and the mammalian two-hybrid system. Our findings show that PHOX2B forms homodimers and heterodimerizes weakly with mutated proteins, exclude the direct involvement of the polyalanine tract in dimer formation, and indicate that mutated proteins retain partial ability to form heterodimers with PHOX2A. Moreover, in this study, we investigated the effects of the longest polyalanine expansions on the homeodomain-mediated nuclear import, and our data clearly show that the expanded C terminus interferes with this process. These results provide novel insights into the effects of the alanine tract expansion on PHOX2B folding and activity.
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