Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2
- Jonathan Nissenbaum1,
- Marshall Devor2,
- Ze'ev Seltzer3,
- Mathias Gebauer4,
- Martin Michaelis4,11,
- Michael Tal5,
- Ruslan Dorfman6,
- Merav Abitbul-Yarkoni7,
- Yan Lu8,
- Tina Elahipanah3,
- Sonia delCanho2,
- Anne Minert2,
- Kaj Fried9,
- Anna-Karin Persson9,
- Hagai Shpigler1,
- Erez Shabo1,
- Benjamin Yakir10,
- Anne Pisanté1 and
- Ariel Darvasi1,12
- 1Department of Genetics, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
- 2Department of Cell and Developmental Biology, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
- 3Centre for the Study of Pain, Faculties of Dentistry and Medicine, University of Toronto, Toronto, Ontario M5G 1G6, Canada;
- 4Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, G879, D-65926 Frankfurt am Main, Germany;
- 5Department of Anatomy and Cell Biology, The Hebrew University of Jerusalem, Jerusalem 91904, Israel;
- 6Hospital for Sick Children, Toronto, Ontario M5G 1X5, Canada;
- 7Faculty of Dentistry, University of Toronto, Ontario M5G 1G6, Canada;
- 8Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada;
- 9Karolinska Institutet, Center for Oral Biology, POB 4064, S-141 04 Huddinge, Sweden;
- 10Department of Statistics, The Hebrew University of Jerusalem, Jerusalem 91904, Israel
Abstract
Chronic neuropathic pain is affected by specifics of the precipitating neural pathology, psychosocial factors, and by genetic predisposition. Little is known about the identity of predisposing genes. Using an integrative approach, we discovered that CACNG2 significantly affects susceptibility to chronic pain following nerve injury. CACNG2 encodes for stargazin, a protein intimately involved in the trafficking of glutamatergic AMPA receptors. The protein might also be a Ca2+ channel subunit. CACNG2 has previously been implicated in epilepsy. Initially, using two fine-mapping strategies in a mouse model (recombinant progeny testing [RPT] and recombinant inbred segregation test [RIST]), we mapped a pain-related quantitative trait locus (QTL) (Pain1) into a 4.2-Mb interval on chromosome 15. This interval includes 155 genes. Subsequently, bioinformatics and whole-genome microarray expression analysis were used to narrow the list of candidates and ultimately to pinpoint Cacng2 as a likely candidate. Analysis of stargazer mice, a Cacng2 hypomorphic mutant, provided electrophysiological and behavioral evidence for the gene's functional role in pain processing. Finally, we showed that human CACNG2 polymorphisms are associated with chronic pain in a cohort of cancer patients who underwent breast surgery. Our findings provide novel information on the genetic basis of neuropathic pain and new insights into pain physiology that may ultimately enable better treatments.
Footnotes
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↵12 Corresponding author.
E-mail arield{at}cc.huji.ac.il; fax 972-2- 5671179.
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[Supplemental material is available online at http://www.genome.org. The human data from this study have been submitted to the Human Genome Variation Database of Genotype-to-Phenotype (http://www.hgvbaseg2.org) under accession no. HGVST514.]
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Article published online before print. Article and publication date are at http://www.genome.org/cgi/doi/10.1101/gr.104976.110.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press
