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Brain. 2018 Feb 1;141(2):365-376. doi: 10.1093/brain/awx326.

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

Author information

Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London, WC1E 6BT, UK.
College of Medicine, Member of Qatar Health Cluster, Qatar University, PO Box 2713, Doha, Qatar.
Department of Molecular Neuroscience, Institute of Neurology, University College London, London, WC1N 3BG, UK.
Department of Medicine, Surgery and Neuroscience, University of Siena, via Aldo Moro, 2, 53100 Siena, Italy.
Department of Biochemistry, Molecular Biology and Immunology, Faculty of Medicine, University of Granada, Granada 18012, Spain.
National Institute for Basic Biology, Okazaki, 444-8585, Japan.
Department of Genetics, Evolution and Environment, University College London, London, WC1E 6BT, UK.
Medical Biology Centre, School of Biological Sciences, Queen's University Belfast, Belfast, BT9 7BL, UK.
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, OX3 9DU, UK.
Department of Physical Sciences, Earth and Environment, University of Siena, 53100 Siena, Italy.


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.


Mendelian; dorsal root ganglia; pain insensitivity; transcription factor

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