Emerillon Therapeutics Inc.

Québec, Canada

Emerillon Therapeutics Inc.

Québec, Canada

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Wiltshire S.A.,McGill University | Diez E.,McGill University | Diez E.,Emerillon Therapeutics Incorporated | Miao Q.,McGill University | And 10 more authors.
Physiological Genomics | Year: 2012

Epidemiological studies show that high HDL-cholesterol (HDLc) decreases the risk of cardiovascular disease. To map genes controlling lipid metabolism, particularly HDLc levels, we screened the plasma lipids of 36 AcB/BcA RC mouse strains subjected to either a normal or a high-fat/cholesterol diet. Strains BcA68 and AcB65 showed deviant HDLc plasma levels compared with the parental A/J and C57BL/6J strains; they were thus selected to generate informative F2 crosses. Linkage analyses in the AcB65 strain identified a locus on chromosome 4 (Hdlq78) responsible for high post-high fat diet HDLc levels. This locus has been previously associated at genome-wide significance to two regions in the human genome. A second linkage analysis in strain BcA68 identified linkage in the vicinity of a gene cluster known to control HDLc levels. Sequence analysis of these candidates identified a de novo, loss-of-function mutation in the ApoA1 gene of BcA68 that prematurely truncates the ApoA1 protein. The possibility of dissecting the specific effects of this new ApoA1 deficiency in the context of isogenic controls makes the BcA68 mouse a valuable new tool. © 2012 the American Physiological Society.


Fortin A.,Emerillon Therapeutics Inc. | Fortin A.,McGill University | Diez E.,Emerillon Therapeutics Inc. | Ritchie J.,McGill University | And 7 more authors.
Genes, Brain and Behavior | Year: 2010

To identify novel pain-relevant genes, a set of 35 recombinant congenic strains derived from the sensitive C57BL/6 and resistant A/J strains were tested for their sensitivity to noxious heat on the radiant heat paw-withdrawal test. Nine strains were found to display differential sensitivity, and the two most extreme responders were used to generate independent secondary crosses for quantitative trait locus (QTL) mapping. From these genetic analyses, a QTL, which we call Tpnr5, was mapped to a 14-Mb interval of mouse chromosome 4 containing 39 genes. In addition to the paw-withdrawal test phenotype, Tpnr5 may be relevant to mechanical and inflammatory nociception. A series of strategies - including in silico analyses, reverse transcriptase polymerase chain reaction (RT-PCR) in multiple tissues and exonic DNA sequencing - were used to generate a list of six prioritized candidate genes. One of these, tyrosinase-related protein 1 (Tyrp1), displayed enriched expression in the dorsal root ganglia, an inactivating (C110Y) mutation in the resistant A/J strain, and a null mutant found to be more resistant to thermal nociception compared to its wild-type counterpart. Although other genes cannot be definitively ruled out, existing data are supportive of the candidacy of Tyrp1 as representing the Tpnr5 QTL. Tyrosinase-related protein 1 is the rate-limiting enzyme in the production of eumelanin, and possible relationships between eumelanin-expressing cells and thermal nociception are discussed. The positional cloning of Tpnr5 is also considered in light of the heuristic value but continuing challenges of QTL mapping in the mouse. © 2010 The Authors. Genes, Brain and Behavior © 2010 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.


PubMed | Emerillon Therapeutics Inc.
Type: Comparative Study | Journal: Genes, brain, and behavior | Year: 2010

To identify novel pain-relevant genes, a set of 35 recombinant congenic strains derived from the sensitive C57BL/6 and resistant A/J strains were tested for their sensitivity to noxious heat on the radiant heat paw-withdrawal test. Nine strains were found to display differential sensitivity, and the two most extreme responders were used to generate independent secondary crosses for quantitative trait locus (QTL) mapping. From these genetic analyses, a QTL, which we call Tpnr5, was mapped to a 14-Mb interval of mouse chromosome 4 containing 39 genes. In addition to the paw-withdrawal test phenotype, Tpnr5 may be relevant to mechanical and inflammatory nociception. A series of strategies - including in silico analyses, reverse transcriptase polymerase chain reaction (RT-PCR) in multiple tissues and exonic DNA sequencing - were used to generate a list of six prioritized candidate genes. One of these, tyrosinase-related protein 1 (Tyrp1), displayed enriched expression in the dorsal root ganglia, an inactivating (C110Y) mutation in the resistant A/J strain, and a null mutant found to be more resistant to thermal nociception compared to its wild-type counterpart. Although other genes cannot be definitively ruled out, existing data are supportive of the candidacy of Tyrp1 as representing the Tpnr5 QTL. Tyrosinase-related protein 1 is the rate-limiting enzyme in the production of eumelanin, and possible relationships between eumelanin-expressing cells and thermal nociception are discussed. The positional cloning of Tpnr5 is also considered in light of the heuristic value but continuing challenges of QTL mapping in the mouse.

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