A novel human pain insensitivity disorder caused by a point mutation in ZFHX2
Open accessAbstract
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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A recent study found a pain insensitivity disorder caused by a mutation in ZFHX2, which carries an AHMC.
“a recent study found a pain insensitivity disorder caused by a mutation in ZFHX2181, which carries an AHMC”
From A catalog of single nucleotide changes distinguishing modern humans from archaic hominins (2019) · cites this paper as [181]
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A catalog of single nucleotide changes distinguishing modern humans from archaic hominins
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- Authors
- Habib, A. M., Matsuyama, A., Okorokov, A. L., Santana-Varela, S., Bras, J. T., Aloisi, A. M., Emery, E. C., Bogdanov, Y. D., Follenfant, M., Gossage, S. J., Gras, M., Humphrey, J., Kolesnikov, A., Le Cann, K., Li, S., Minett, M. S., Pereira, V., Ponsolles, C., Sikandar, S., Torres, J. M., Yamaoka, K., Zhao, J., Komine, Y., Yamamori, T., Maniatis, N., Panov, K. I., Houlden, H., Ramirez, J. D., Bennett, D. L. H., Marsili, L., Bachiocco, V., Wood, J. N., & Cox, J. J.
- Affiliations
- University College London (GB)
- Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, UK
- Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK
- University of Siena (IT)
- National Institute for Basic Biology (JP)
- Medical Biology Centre, School of Biological Sciences, Queen’s University Belfast, Belfast, UK
- UCL Queen Square Institute of Neurology (GB)
- University of Oxford (GB)
- Corresponding author
- Cox, James J
- ORCID
- Habib, Abdella M
- Okorokov, Andrei L
- Aloisi, Anna Maria
- Emery, Edward C
- Bogdanov, Yury D
- Humphrey, Jack
- Kolesnikov, Anna
- Li, Shengnan
- Pereira, Vanessa
- Ponsolles, Clara
- Sikandar, Shafaq
- Yamaoka, Kenji
- Zhao, Jing
- Komine, Yuriko
- Yamamori, Tetsuo
- Maniatis, Nikolas
- Houlden, Henry
- Ramirez, Juan D
- Bennett, David L H
- Marsili, Letizia
- Wood, John N
- Cox, James J
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-12-14
- Volume
- 141
- Issue
- 2
- Pages
- 365-376
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC5837393
- OpenAlex
- W2772249211
- Cited by
- 50
- References
- 52
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 8 · 2023: 4 · 2022: 6 · 2021: 4 · 2020: 6 · 2019: 9 · 2018: 5
- FWCI
- 4.05
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Qatar University QSpace (Qatar University) (submittedVersion)
- Use Siena air (University of Siena) (submittedVersion, cc-by)
- Funders
- Medical Research Council (G1100340)
- Wellcome Trust (200183/Z/15/Z and 101054/Z/13/Z)
- Arthritis Research UK (20200)
- Shionogi (165302)
- Wellcome (095698z/11/z and 202747/Z/16/Z)
- Topics
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Keywords
- pain insensitivity, point mutations, chronic pain, analgesic targets, homeodomain, sensory neurons, dorsal root ganglia, BAC transgenic mice, autosomal dominant disorder
- MeSH terms
- Zinc Finger E-box Binding Homeobox 2, Action Potentials, Adolescent, Adult, Aged, Pain Insensitivity, Congenital, Animals, Calcium, Capsaicin, Disease Models, Animal, Female, Ganglia, Spinal, Gene Expression Regulation, Humans, Hyperalgesia, Male, Mice, Inbred C57BL, Middle Aged, Pain, Sensory Receptor Cells, Skin, Pain Threshold, Point Mutation, Mice, Knockout, Mice, Young Adult
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