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

Abdella M Habib, Ayako Matsuyama, Andrei L Okorokov, Sonia Santana-Varela, Jose T Bras, Anna Maria Aloisi, Edward C Emery, Yury D Bogdanov, Maryne Follenfant, Sam J Gossage, Mathilde Gras, Jack Humphrey, Anna Kolesnikov, Kim Le Cann, Shengnan Li, Michael S Minett, Vanessa Pereira, Clara Ponsolles, Shafaq Sikandar, Jesus M Torres & 13 others Kenji Yamaoka, Jing Zhao, Yuriko Komine, Tetsuo Yamamori, Nikolas Maniatis, Konstantin I Panov, Henry Houlden, Juan D Ramirez, David L H Bennett, Letizia Marsili, Valeria Bachiocco, John N Wood, James J Cox

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

LanguageEnglish
JournalBrain
Early online date14 Dec 2017
DOIs
Publication statusEarly online date - 14 Dec 2017
Externally publishedYes

Fingerprint

Somatoform Disorders
Point Mutation
Pain
Analgesics
Exome
Phenotype
Bacterial Artificial Chromosomes
Gene Expression
Mutation
Bone Fractures
Spinal Ganglia
Peripheral Nervous System Diseases
Sensory Receptor Cells
Chronic Pain
Transgenic Mice
Lysine
Arginine
Transcription Factors
Public Health
Hot Temperature

Keywords

  • Journal Article

Cite this

Habib, A. M., Matsuyama, A., Okorokov, A. L., Santana-Varela, S., Bras, J. T., Aloisi, A. M., ... Cox, J. J. (2017). A novel human pain insensitivity disorder caused by a point mutation in ZFHX2. Brain. https://doi.org/10.1093/brain/awx326
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 ; Cox, James J. / A novel human pain insensitivity disorder caused by a point mutation in ZFHX2. In: Brain. 2017.
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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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Habib, AM, Matsuyama, A, Okorokov, AL, Santana-Varela, S, Bras, JT, Aloisi, AM, Emery, EC, Bogdanov, YD, Follenfant, M, Gossage, SJ, Gras, M, Humphrey, J, Kolesnikov, A, Le Cann, K, Li, S, Minett, MS, Pereira, V, Ponsolles, C, Sikandar, S, Torres, JM, Yamaoka, K, Zhao, J, Komine, Y, Yamamori, T, Maniatis, N, Panov, KI, Houlden, H, Ramirez, JD, Bennett, DLH, Marsili, L, Bachiocco, V, Wood, JN & Cox, JJ 2017, 'A novel human pain insensitivity disorder caused by a point mutation in ZFHX2', Brain. https://doi.org/10.1093/brain/awx326

A novel human pain insensitivity disorder caused by a point mutation in ZFHX2. / 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; Cox, James J.

In: Brain, 14.12.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel human pain insensitivity disorder caused by a point mutation in ZFHX2

AU - Habib, Abdella M

AU - Matsuyama, Ayako

AU - Okorokov, Andrei L

AU - Santana-Varela, Sonia

AU - Bras, Jose T

AU - Aloisi, Anna Maria

AU - Emery, Edward C

AU - Bogdanov, Yury D

AU - Follenfant, Maryne

AU - Gossage, Sam J

AU - Gras, Mathilde

AU - Humphrey, Jack

AU - Kolesnikov, Anna

AU - Le Cann, Kim

AU - Li, Shengnan

AU - Minett, Michael S

AU - Pereira, Vanessa

AU - Ponsolles, Clara

AU - Sikandar, Shafaq

AU - Torres, Jesus M

AU - Yamaoka, Kenji

AU - Zhao, Jing

AU - Komine, Yuriko

AU - Yamamori, Tetsuo

AU - Maniatis, Nikolas

AU - Panov, Konstantin I

AU - Houlden, Henry

AU - Ramirez, Juan D

AU - Bennett, David L H

AU - Marsili, Letizia

AU - Bachiocco, Valeria

AU - Wood, John N

AU - Cox, James J

N1 - © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain.

PY - 2017/12/14

Y1 - 2017/12/14

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1093/brain/awx326

DO - 10.1093/brain/awx326

M3 - Article

JO - Brain

T2 - Brain

JF - Brain

SN - 0006-8950

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Habib AM, Matsuyama A, Okorokov AL, Santana-Varela S, Bras JT, Aloisi AM et al. A novel human pain insensitivity disorder caused by a point mutation in ZFHX2. Brain. 2017 Dec 14. https://doi.org/10.1093/brain/awx326