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PloS one 2013;8(2):e56260. doi: 10.1371/journal.pone.0056260. Epub 2013 Feb 15.

Pregnancy Associated Plasma Protein A2 (PAPP-A2) Affects Bone Size and Shape and Contributes to Natural Variation in Postnatal Growth in Mice.

Christians, JK; de Zwaan, DR; Fung, SH

Biological Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.

Pregnancy associated plasma protein A2 (PAPP-A2) is a protease of insulin-like growth factor binding protein 5 and is receiving increasing attention for its roles in pregnancy and postnatal growth. The goals of the present study were to characterize the effects of PAPP-A2 deletion on bone size and shape in mice at 10 weeks of age, and to determine whether is the gene responsible for a previously-identified quantitative trait locus (QTL) contributing to natural variation in postnatal growth in mice. Mice homozygous for constitutive PAPP-A2 deletion were lighter than wild-type littermates, and had smaller mandible dimensions and shorter skull, humerus, femur, tibia, pelvic girdle, and tail bone. Furthermore, PAPP-A2 deletion reduced mandible dimensions and the lengths of the skull, femur, pelvic girdle, and tail bone more than would be expected due to the effect on body mass. In addition to its effects on bone size, PAPP-A2 deficiency also altered the shape of the mandible and pelvic girdle, as assessed by geometric morphometrics. Mice homozygous for the PAPP-A2 deletion had less deep mandibles, and pelvic girdles with a more feminine shape. Using a quantitative complementation test, we confirmed that is responsible for the effects of the previously-identified QTL, demonstrating that natural variation in the gene contributes to variation in postnatal growth in mice. If similar functional variation in the gene exists in other species, effects of this variation on the shape of the pelvic girdle might explain the previously-reported associations between SNPs and developmental dysplasia of the hip in humans, and birthing in cattle.

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