In previous studies using the Neuroma model we identified a quantitative trait locus (QTL), , that affects predisposition to this pain phenotype and mapped it to an ∼25-c M interval on chromosome 15 (Seltzer et al. We accomplished this aim by implementing a broad, integrative approach that included fine-mapping experiments followed by application of several strategies for prioritizing candidate genes.
The gene identified in this way is encodes for the gamma-2 transmembrane AMPA receptor protein (TARP) stargazin, known to be intimately involved in the trafficking of glutamatergic AMPA receptors and the modulation of their ion channel function (Priel et al. 2007; Cokic and Stein 2008; Milstein and Nicoll 2009).
The columns “NIS” (NI, nerve-injured; S, sham) and “H-L” (H, high autotomy; L, low autotomy) highlight genes with significant expression-fold change (the direction of the arrowheads indicates up-regulation or down-regulation).
The “NI-S” column presents the results for the nerve-injured versus sham comparison, and the “H-L” column presents the results for the high-autotomy versus the low-autotomy strains. Whole-genome expression analyses were obtained for the L5 dorsal root ganglion (L5DRG) of 73 individual mice of five different mouse strains: AKR/J, C3H/He J, CBA/J, C57BL/6J, and C58/J.
In both cases, the F offspring were backcrossed to the recessive A/J strain.
For each of the resulting four BC populations, female mice were phenotyped for autotomy and then genotyped at a single SNP selected to be both polymorphic in the BC mice used and relatively close to the recombination breakpoint in the relevant RI strain (Fig. As appropriate, a different SNP was used for each of the four BC populations.
(Blue bars) SNPs with a complete cosegregation among the seven mouse strains (see text); (dark blue bars) coding nonsynonymous SNPs; (light blue) other SNPs.
Autotomy behavior is highly variable among individuals and across inbred strains. No other significant QTLs were found in a whole-genome scan (Devor et al. Mapping QTLs to specific chromosomal regions is only the first step toward the ultimate goal of identifying the underlying gene(s), the aim of the present study.In parallel with RPT, RIST experiments were carried out using BXA7 and BXA8, two recombinant inbred (RI) strains known to have recombinations in the region of .In RIST, the genotypic state of the QTL in each recombinant strain is assessed, localizing the QTL to a defined chromosomal interval (Darvasi 1998).It also modulates neuronal Ca is known to play a role in cerebellar function and in epilepsy, but not neuropathic pain.We have now established that it also plays a functional role, in both mice and humans, in the heritable predisposition to neuropathic pain.2005), results of this phenotyping can establish the genotypic state of 1), for the progeny of each of the recombinant progenitor mice.