TY - JOUR
T1 - A novel disorder reveals clathrin heavy chain-22 is essential for human pain and touch development
AU - Nahorski, Michael S.
AU - Al-Gazali, Lihadh
AU - Hertecant, Jozef
AU - Owen, David J.
AU - Borner, Georg H.H.
AU - Chen, Ya Chun
AU - Benn, Caroline L.
AU - Carvalho, Ofélia P.
AU - Shaikh, Samiha S.
AU - Phelan, Anne
AU - Robinson, Margaret S.
AU - Royle, Stephen J.
AU - Woods, C. Geoffrey
N1 - Publisher Copyright:
© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain.
PY - 2015/8/1
Y1 - 2015/8/1
N2 - 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.
AB - 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.
KW - clathrin
KW - endosomal trafficking
KW - insensitivity to pain
KW - neurogenesis
UR - http://www.scopus.com/inward/record.url?scp=84940061598&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84940061598&partnerID=8YFLogxK
U2 - 10.1093/brain/awv149
DO - 10.1093/brain/awv149
M3 - Article
C2 - 26068709
AN - SCOPUS:84940061598
SN - 0006-8950
VL - 138
SP - 2147
EP - 2160
JO - Brain
JF - Brain
IS - 8
ER -