Quantitative trait loci for biomechanical performance and femoral geometry in an intercross of recombinant congenic mice: restriction of the Bmd7 candidate interval.
Despite steady progress in identifying quantitative trait loci (QTLs) for bone phenotypes, relatively little progress has been made in moving from QTLs to identifying the relevant gene. We exploited the genetic structure of recombinant congenic mouse strains by performing a reciprocal intercross of the strains HcB-8 and HcB-23, phenotyped for body size, femoral biomechanical performance, and femoral diaphyseal geometry and mapped with R/qtl and QTL Cartographer. Significant QTLs are present on chromosomes 1, 2, 3, 4, 6, and 10. We found significant sex x QTL and cross-direction x QTL interactions. The chromosome 4 QTL affects multiple femoral anatomic features and biomechanical properties. The known segregating segment of chromosome 4 contains only 18 genes, among which Ece1, encoding endothelin-converting enzyme 1, stands out as a candidate. Endothelin signaling has been shown to promote the growth of osteoblastic metastases and to potentiate signaling via the Wnt pathway. The colocalizing chromosome 4 QTL Bmd7 (for bone mineral density 7) increases responsiveness to mechanical loading. By exploiting the short informative segment of chromosome 4 and the known biology, we propose that Ece1 is the gene responsible for Bmd7 and that it acts by increasing responsiveness to mechanical loading through modulation of Wnt signaling.
Saless
Neema
N
University of Wisconsin, Madison, Wisconsin, USA.
Litscher
Suzanne J
SJ
Lopez Franco
Gloria E
GE
Houlihan
Meghan J
MJ
Sudhakaran
Shaan
S
Raheem
Khalid Abdul
KA
O'Neil
Tyriina K
TK
Vanderby
Ray
R
Demant
Peter
P
Blank
Robert D
RD
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000502:physiology; D001696:Biomechanical Phenomena / Q000235:genetics; D015519:Bone Density / Q000235:genetics; D033481:Chromosomes, Mammalian; D003433:Crosses, Genetic; D000072396:Endothelin-Converting Enzymes; D005260:Female; D005269:Femur / Q000033:anatomy & histology / Q000502:physiology*; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics* / Q000502:physiology; D051379:Mice; D020297:Mice, Congenic; D010641:Phenotype; D040641:Quantitative Trait Loci; D012730:Sex Chromosomes; D051153:Wnt Proteins / Q000378:metabolism
D051153:Wnt Proteins; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606925:Ece1 protein, mouse; D000072396:Endothelin-Converting Enzymes