PAPPA2, an enzyme that cleaves an insulin-like growth-factor-binding protein, is a candidate gene for a quantitative trait locus affecting body size in mice

Identifying genes responsible for quantitative variation remains a major challenge. We previously identified a quantitative trait locus (QTL) affecting body size that segregated between two inbred strains of mice. By fine mapping, we have refined the location of this QTL to a genomic region containing only four protein-coding genes. One of these genes, PAPPA2, is a strong candidate because it codes for an enzyme that cleaves insulin-like growth-factor-binding protein 5 (IGFBP-5), an important stimulator of bone formation. Among littermates that segregate only for the four-gene region, we show that the QTL has a significant effect on the circulating levels of IGFBP-5 and IGFBP-3 (the latter subject to limited degradation by PAPPA2), but not on levels of IGFBP-2 and IGFBP-4, which are not cleaved by PAPPA2. There are 14 nonsynonymous SNPs among QTL alleles, which may affect the activity of the translated protein. The refinement of the target region to four genes and the finding that the QTL affects IGFBP-5 levels suggest that PAPPA2 may be involved with normal postnatal growth. Our mapping results also illustrate the potentially fractal nature of QTL: as we mapped our QTL with increasing resolution, what appeared to be a single QTL resolved into three closely linked QTL (previous work), and then one of these was further dissected into two in this study.