English
 
Help Privacy Policy Disclaimer
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  A novel disorder reveals clathrin heavy chain-22 is essential for human pain and touch development

Nahorski, M. S., Al-Gazali, L., Hertecant, J., Owen, D. J., Borner, G. H. H., Chen, Y.-C., et al. (2015). A novel disorder reveals clathrin heavy chain-22 is essential for human pain and touch development. BRAIN, 138, 2147-2160. doi:10.1093/brain/awv149.

Item is

Files

show Files
hide Files
:
2147.full.pdf (Any fulltext), 2MB
Name:
2147.full.pdf
Description:
-
Visibility:
Public
MIME-Type / Checksum:
application/pdf / [MD5]
Technical Metadata:
Copyright Date:
-
Copyright Info:
open access article
License:
-

Locators

show

Creators

show
hide
 Creators:
Nahorski, Michael S.1, Author
Al-Gazali, Lihadh1, Author
Hertecant, Jozef1, Author
Owen, David J.1, Author
Borner, Georg H. H.2, Author              
Chen, Ya-Chun1, Author
Benn, Caroline L.1, Author
Carvalho, Ofelia P.1, Author
Shaikh, Samiha S.1, Author
Phelan, Anne1, Author
Robinson, Margaret S.1, Author
Royle, Stephen J.1, Author
Woods, C. Geoffrey1, Author
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

Content

show
hide
Free keywords: DOMAIN BETA-PROPELLER; TERMINAL DOMAIN; HUMAN BRAIN; NEUROBLASTOMA-CELLS; RETINOIC ACID; ISOFORM CHC22; MECHANISMS; GENE; DIFFERENTIATION; TRANSCRIPTOMEinsensitivity to pain; clathrin; endosomal trafficking; neurogenesis;
 Abstract: Congenital inability to feel pain is rare, but the identification of causative genes is translating into the development of novel analgesics. Nahorski <italic toggle="yes">et al. describe insensitivity to pain caused by mutations affecting the second clathrin heavy chain (CHC22), and reveal a role for CHC22 in pain and touch development.Congenital inability to feel pain is rare, but the identification of causative genes is translating into the development of novel analgesics. Nahorski <italic toggle="yes">et al. describe insensitivity to pain caused by mutations affecting the second clathrin heavy chain (CHC22), and reveal a role for CHC22 in pain and touch development.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 <italic toggle="yes">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.

Details

show
hide
Language(s): eng - English
 Dates: 2015
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: ISI: 000360578700015
DOI: 10.1093/brain/awv149
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: BRAIN
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND : OXFORD UNIV PRESS
Pages: - Volume / Issue: 138 Sequence Number: - Start / End Page: 2147 - 2160 Identifier: ISSN: 0006-8950