Nahorski, Michael S., Al-Gazali, Lihadh, Hertecant, Jozef, Owen, David J., Borner, Georg H. H., Chen, Ya-Chun, Benn, Caroline L., Carvalho, Ofélia P., Shaikh, Samiha S., Phelan, Anne, Robinson, Margaret S., Royle, Stephen J. and Woods, C. Geoffrey (2015) A novel disorder reveals clathrin heavy chain-22 is essential for human pain and touch development. Brain, 138 (8). pp. 2147-2160. doi:10.1093/brain/awv149 ISSN 0006-8950.
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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.
Item Type: | Journal Article |
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Subjects: | Q Science > QP Physiology R Medicine > RC Internal medicine |
Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Cell & Developmental Biology Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
Library of Congress Subject Headings (LCSH): | Developmental neurobiology , Congenital insensitivity to pain |
Journal or Publication Title: | Brain |
Publisher: | Oxford University Press |
ISSN: | 0006-8950 |
Official Date: | 11 June 2015 |
Dates: | Date Event 11 June 2015 Published 4 April 2015 Accepted 2 March 2015 Submitted |
Volume: | 138 |
Number: | 8 |
Page Range: | pp. 2147-2160 |
DOI: | 10.1093/brain/awv149 |
Status: | Peer Reviewed |
Publication Status: | Published |
Access rights to Published version: | Open Access (Creative Commons open licence) |
Funder: | Medical Research Council (Great Britain) (MRC), Wellcome Trust (London, England), Cancer Research UK (CRUK), National Institute for Health Research (Great Britain). Biomedical Research Centre |
URI: | https://wrap.warwick.ac.uk/84966/ |
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