RRC ID 53849
著者 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.
タイトル A novel human pain insensitivity disorder caused by a point mutation in ZFHX2.
ジャーナル Brain
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.
巻・号 141(2)
ページ 365-376
公開日 2018-2-1
DOI 10.1093/brain/awx326
PII 4725107
PMID 29253101
PMC PMC5837393
MeSH Action Potentials / drug effects Action Potentials / physiology Adolescent Adult Aged Animals Calcium / metabolism Capsaicin / adverse effects Disease Models, Animal Female Ganglia, Spinal / pathology Gene Expression Regulation / drug effects Gene Expression Regulation / genetics Humans Hyperalgesia / pathology Hyperalgesia / physiopathology Male Mice Mice, Inbred C57BL Mice, Knockout Middle Aged Pain / chemically induced Pain / physiopathology* Pain Insensitivity, Congenital / genetics* Pain Insensitivity, Congenital / pathology Pain Insensitivity, Congenital / physiopathology Pain Threshold / physiology* Point Mutation / genetics* Sensory Receptor Cells / drug effects Sensory Receptor Cells / physiology Skin / pathology Young Adult Zinc Finger E-box Binding Homeobox 2 / genetics*
IF 11.337
引用数 8
リソース情報
実験動物マウス RBRC02262