Pbd2^SAMP2
QTL Variant Detail

Summary

• QTL variant: Pbd2^SAMP2
• Name: peak bone density 2; SAMP2
• MGI ID: MGI:2389308
• QTL: Pbd2 Location: Chr13:17189508-38947406 bp Genetic Position: Chr13, cM position of peak correlated region/allele: 12.94 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: SAMP2

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased bone density compared to SAMP6. (J:75819)

Expression

In Structures Affected by this Mutation:

2 anatomical structure(s)

Notes

Candidate Genes

J:77538

The authors report the construction of a reciprocal congenic strain, P2.P6-Pbd2^a. Strains SAMP6 and SAMP2 were used as the donor and recipient strains, respectively. Whereas Pbd2 is a QTL locus defined by bone mass. The Congenic strain carries a SAMP6-derived mouse Chromosome 13 osteoporosis susceptible interval within the SAMP2-derived osteoporosis resistance background. The Interval could be defined as being contained within proximal marker D13Mit303 and distal marker D13Mit177. Within this region gene Bmp6 resides which is suggested as a candidate gene for Pbd2.

Mapping and Phenotype information for this QTL, its variants and associated markers

J:52867

90 polymorphic loci were screened in animals from a (SAMP2/Clea x SAMP6/Clea)F2 intercross using a selective genotyping strategy to identify QTLs involved in peak bone mass. SAM (Senescence Accelerated Mouse) inbred strain SAMP6 exhibits lower peak bone mass compared to the SAMP2 inbred strain. Significant loci were detected on mouse Chromosome 13 (Pbd2, LOD = 5.8 at 8.3 cM) with a QTL interval spanning 9 cM - 10 cM, and mouse Chromosome 11 (Pbd1, LOD = 10.8 at 51.8 cM) with a QTL interval spanning 42 cM - 58.51 cM. Possible candidate genes for Pbd1 are Col1a1 (Cola1) and Csf3 (Csfg). Suggestive loci were also detected on mouse chromosome 9 and mouse Chromosome X at 49 cM in linkage with DXMit97.

J:75819

Pbd2, a QTL associated with peak bone density, was confirmed using congenic strain P6.P2-Pbd2^b. P6.P2-Pbd2^b carries a 15 cM interval of mouse Chromosome 13 derived from the high bone density SAMP2 strain on the genetic background of the osteoporotic strain SAMP6. This 15 cM congenic region encompasses markers D13Mit174, D13Mit135, D13Mit115, D13Mit266, D13Mit60, D13Mit117, D13Mit177, and D13Mit88. The congenic strain indeed exhibits increased bone density compared to the osteoporotic SAMP6 backgroundstrain, thus confirming the presence of the Pbd2 QTL. A possible candidate gene, Inhba, found at 10 cM on chromosome 13, was investigated but no difference in expression between SAMP2 and SAMP6 could be found. Another candidate gene is Bmp6, found at 20 cM on chromosome 13. Polymorphisms in Bmp6 exist between strains SAMP2 and SAMP6 and this candidate gene is being studied further.

J:115910

Pbd2, a QTL associated with peak bone density, maps to 14.5 cM on mouse Chromosome 13. This locus was further refined using a congenic subline derived from P6.P2-Pbd2^b. The congenic subline is called P6.P2-13 and carries a 2.4 Mb interval derived from SAMP2 (a high bone density strain) on the genetic background of SAMP6 (an osteoporotic strain). The congenic interval extends from 17.46 Mb to 19.86 Mb. The right femurs of male congenic and SAMP6 animals were phenotyped at 4 months of age.

Male P6.P2-13 animals exhibit increased bone volume at the metaphysis, increased cortical thickness at the diaphysis, and significantly increased periosteal mineralizing surface compared to male SAMP6 animals. Eleven genes map to the 2.4 Mb congenic interval. Sfrp4 (7 cM) is a candidate gene in this region. In vitro mRNA assay showed significantly increased Sfrp4 expression in SAMP6 cultured osteoblasts compared to P6.P2-13 cultured osteoblasts. Analysis SAMP2 and SAMP6 sequences detected a conservative polymorphism inthe Sfrp4 coding region and 14 nucleotide polymorphism in the putative promoter region. The congenic region of P6.P2-13 is syntenic to human Chromosome 17p14, a region associated with bone mineral density in humans.

References

• Original: J:75819 Shimizu M, et al., Chromosome 13 locus, Pbd2, regulates bone density in mice. J Bone Miner Res. 2001 Nov;16(11):1972-82
• All: 4 reference(s)