This contrasts with the in vivo situation, where we find that even massive overaccumulation of 1-IP7 by ablation of DDP1 cannot trigger the PHO pathway, but where suppression of 5-IP7 and 1,5-IP8 production by ablation of KCS1 does activate it constitutively (Figure 4; Auesukaree et al., 2005). This evidence concerns the gene TIMM8A and primary hypertrophic osteoarthropathy.