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A novel human pain insensitivity disorder caused by a point mutation in ZFHX2

A novel human pain insensitivity disorder caused by a point mutation in ZFHX2
A novel human pain insensitivity disorder caused by a point mutation in ZFHX2

Chronic pain is a major global public health issue causing a severe impact on both the quality of life for sufferers and the wider economy. Despite the significant clinical burden, little progress has been made in terms of therapeutic development. A unique approach to identifying new human-validated analgesic drug targets is to study rare families with inherited pain insensitivity. Here we have analysed an otherwise normal family where six affected individuals display a pain insensitive phenotype that is characterized by hyposensitivity to noxious heat and painless bone fractures. This autosomal dominant disorder is found in three generations and is not associated with a peripheral neuropathy. A novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons, was identified by whole exome sequencing that segregates with the pain insensitivity. The mutation is predicted to change an evolutionarily highly conserved arginine residue 1913 to a lysine within a homeodomain. Bacterial artificial chromosome (BAC) transgenic mice bearing the orthologous murine p.R1907K mutation, as well as Zfhx2 null mutant mice, have significant deficits in pain sensitivity. Gene expression analyses in dorsal root ganglia from mutant and wild-type mice show altered expression of genes implicated in peripheral pain mechanisms. The ZFHX2 variant and downstream regulated genes associated with a human pain-insensitive phenotype are therefore potential novel targets for the development of new analgesic drugs.awx326media15680039660001.

Journal Article
0006-8950
365-376
Habib, Abdella M.
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Matsuyama, Ayako
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Okorokov, Andrei L.
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Santana-Varela, Sonia
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Bras, Jose T.
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Aloisi, Anna Maria
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Emery, Edward C.
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Bogdanov, Yury D
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Follenfant, Maryne
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Gossage, Sam J.
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Gras, Mathilde
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Humphrey, Jack
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Kolesnikov, Anna
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Le Cann, Kim
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Li, Shengnan
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Minett, Michael S.
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Pereira, Vanessa
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Ponsolles, Clara
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Sikandar, Shafaq
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Torres, Jesus M.
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Yamaoka, Kenji
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Zhao, Jing
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Komine, Yuriko
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Yamamori, Tetsuo
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Maniatis, Nikolas
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Panov, Konstantin I
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Houlden, Henry
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Ramirez, Juan D.
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Bennett, David L.H.
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Marsili, Letizia
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Bachiocco, Valeria
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Wood, John N.
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Cox, James J.
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Habib, Abdella M.
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Matsuyama, Ayako
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Okorokov, Andrei L.
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Santana-Varela, Sonia
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Bras, Jose T.
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Aloisi, Anna Maria
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Emery, Edward C.
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Bogdanov, Yury D
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Follenfant, Maryne
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Gossage, Sam J.
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Gras, Mathilde
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Humphrey, Jack
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Kolesnikov, Anna
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Le Cann, Kim
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Li, Shengnan
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Minett, Michael S.
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Pereira, Vanessa
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Ponsolles, Clara
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Sikandar, Shafaq
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Torres, Jesus M.
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Yamaoka, Kenji
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Zhao, Jing
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Komine, Yuriko
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Yamamori, Tetsuo
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Maniatis, Nikolas
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Panov, Konstantin I
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Houlden, Henry
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Ramirez, Juan D.
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Bennett, David L.H.
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Marsili, Letizia
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Bachiocco, Valeria
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Wood, John N.
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Cox, James J.
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Habib, Abdella M., Matsuyama, Ayako, Okorokov, Andrei L., Santana-Varela, Sonia, Bras, Jose T., Aloisi, Anna Maria, Emery, Edward C., Bogdanov, Yury D, Follenfant, Maryne, Gossage, Sam J., Gras, Mathilde, Humphrey, Jack, Kolesnikov, Anna, Le Cann, Kim, Li, Shengnan, Minett, Michael S., Pereira, Vanessa, Ponsolles, Clara, Sikandar, Shafaq, Torres, Jesus M., Yamaoka, Kenji, Zhao, Jing, Komine, Yuriko, Yamamori, Tetsuo, Maniatis, Nikolas, Panov, Konstantin I, Houlden, Henry, Ramirez, Juan D., Bennett, David L.H., Marsili, Letizia, Bachiocco, Valeria, Wood, John N. and Cox, James J. (2018) A novel human pain insensitivity disorder caused by a point mutation in ZFHX2. Brain, 141 (2), 365-376. (doi:10.1093/brain/awx326).

Record type: Article

Abstract

Chronic pain is a major global public health issue causing a severe impact on both the quality of life for sufferers and the wider economy. Despite the significant clinical burden, little progress has been made in terms of therapeutic development. A unique approach to identifying new human-validated analgesic drug targets is to study rare families with inherited pain insensitivity. Here we have analysed an otherwise normal family where six affected individuals display a pain insensitive phenotype that is characterized by hyposensitivity to noxious heat and painless bone fractures. This autosomal dominant disorder is found in three generations and is not associated with a peripheral neuropathy. A novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons, was identified by whole exome sequencing that segregates with the pain insensitivity. The mutation is predicted to change an evolutionarily highly conserved arginine residue 1913 to a lysine within a homeodomain. Bacterial artificial chromosome (BAC) transgenic mice bearing the orthologous murine p.R1907K mutation, as well as Zfhx2 null mutant mice, have significant deficits in pain sensitivity. Gene expression analyses in dorsal root ganglia from mutant and wild-type mice show altered expression of genes implicated in peripheral pain mechanisms. The ZFHX2 variant and downstream regulated genes associated with a human pain-insensitive phenotype are therefore potential novel targets for the development of new analgesic drugs.awx326media15680039660001.

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Accepted/In Press date: 18 October 2017
e-pub ahead of print date: 14 December 2017
Published date: 1 February 2018
Additional Information: © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.
Keywords: Journal Article

Identifiers

Local EPrints ID: 417825
URI: https://eprints.soton.ac.uk/id/eprint/417825
ISSN: 0006-8950
PURE UUID: e3d19ddc-4ab0-485a-8528-7feaf298b807
ORCID for Yury D Bogdanov: ORCID iD orcid.org/0000-0003-4667-5890

Catalogue record

Date deposited: 15 Feb 2018 17:30
Last modified: 14 Mar 2019 01:32

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Contributors

Author: Abdella M. Habib
Author: Ayako Matsuyama
Author: Andrei L. Okorokov
Author: Sonia Santana-Varela
Author: Jose T. Bras
Author: Anna Maria Aloisi
Author: Edward C. Emery
Author: Yury D Bogdanov ORCID iD
Author: Maryne Follenfant
Author: Sam J. Gossage
Author: Mathilde Gras
Author: Jack Humphrey
Author: Anna Kolesnikov
Author: Kim Le Cann
Author: Shengnan Li
Author: Michael S. Minett
Author: Vanessa Pereira
Author: Clara Ponsolles
Author: Shafaq Sikandar
Author: Jesus M. Torres
Author: Kenji Yamaoka
Author: Jing Zhao
Author: Yuriko Komine
Author: Tetsuo Yamamori
Author: Nikolas Maniatis
Author: Konstantin I Panov
Author: Henry Houlden
Author: Juan D. Ramirez
Author: David L.H. Bennett
Author: Letizia Marsili
Author: Valeria Bachiocco
Author: John N. Wood
Author: James J. Cox

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