ArticleBrain : a journal of neurology2015
A novel disorder reveals clathrin heavy chain-22 is essential for human pain and touch development.
Article in Brain : a journal of neurology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 53 citations in OpenAlex.
- Brain-Derived Neurotrophic Factor Trafficking via the Regulated Secretory Pathway: Mechanisms and Disease Implications.Molecular neurobiology · 2025Review
- Mechanistic divergences of endocytic clathrin-coated vesicle formation in mammals, yeasts and plants.Journal of cell science · 2024Review
- Pathology of pain and its implications for therapeutic interventions.Signal transduction and targeted therapy · 2024Review
- The AP-2 complex interacts with γ-TuRC and regulates the proliferative capacity of neural progenitors.Life science alliance · 2024Article
- Genetic pain loss disorders.Nature reviews. Disease primers · 2022Review
- Selected Ionotropic Receptors and Voltage-Gated Ion Channels: More Functional Competence for Human Induced Pluripotent Stem Cell (iPSC)-Derived Nociceptors.Brain sciences · 2020Article
- Understanding the genetic basis of congenital insensitivity to pain.British medical bulletin · 2020Review
- CHC22 clathrin mediates traffic from early secretory compartments for human GLUT4 pathway biogenesis.The Journal of cell biology · 2020Article
- Pathobiology of Christianson syndrome: Linking disrupted endosomal-lysosomal function with intellectual disability and sensory impairments.Neurobiology of learning and memory · 2019Article
- Coatopathies: Genetic Disorders of Protein Coats.Annual review of cell and developmental biology · 2019Review
- In the line-up: deleted genes associated with DiGeorge/22q11.2 deletion syndrome: are they all suspects?Journal of neurodevelopmental disorders · 2019Review
- Article
- Risk gene-set and pathways in 22q11.2 deletion-related schizophrenia: a genealogical molecular approach.Translational psychiatry · 2019Article
- Meta-Analysis of Gene Expression and Identification of Biological Regulatory Mechanisms in Alzheimer's Disease.Frontiers in neuroscience · 2019Article
- Phosphoinositides: Regulators of Nervous System Function in Health and Disease.Frontiers in molecular neuroscience · 2019Review
- Clathrin heavy chain 22 contributes to the control of neuropeptide degradation and secretion during neuronal development.Scientific reports · 2018Article
- CHC22 and CHC17 clathrins have distinct biochemical properties and display differential regulation and function.The Journal of biological chemistry · 2017Article
- Identification of novel candidate disease genes from de novo exonic copy number variants.Genome medicine · 2017Article
- A Comprehensive Functional Analysis of NTRK1 Missense Mutations Causing Hereditary Sensory and Autonomic Neuropathy Type IV (HSAN IV).Human mutation · 2017Article
- Integrated Computational Analysis of Genes Associated with Human Hereditary Insensitivity to Pain. A Drug Repurposing Perspective.Frontiers in molecular neuroscience · 2017Article
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Authors and funding
13 authors at 4 institutions in 3 countries.
Funding
Abstract
Congenital inability to feel pain is very rare but the identification of causative genes has yielded significant insights into pain pathways and also novel targets for pain treatment. We report a novel recessive disorder characterized by congenital insensitivity to pain, inability to feel touch, and cognitive delay. Affected individuals harboured a homozygous missense mutation in CLTCL1 encoding the CHC22 clathrin heavy chain, p.E330K, which we demonstrate to have a functional effect on the protein. We found that CLTCL1 is significantly upregulated in the developing human brain, displaying an expression pattern suggestive of an early neurodevelopmental role. Guided by the disease phenotype, we investigated the role of CHC22 in two human neural crest differentiation systems; human induced pluripotent stem cell-derived nociceptors and TRKB-dependant SH-SY5Y cells. In both there was a significant downregulation of CHC22 upon the onset of neural differentiation. Furthermore, knockdown of CHC22 induced neurite outgrowth in neural precursor cells, which was rescued by stable overexpression of small interfering RNA-resistant CHC22, but not by mutant CHC22. Similarly, overexpression of wild-type, but not mutant, CHC22 blocked neurite outgrowth in cells treated with retinoic acid. These results reveal an essential and non-redundant role for CHC22 in neural crest development and in the genesis of pain and touch sensing neurons.
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Registered trials
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