David M. Kingsley, Ph.D.
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Skeletal Disease

Arthritis, one of the most prevalent diseases in humans, is clearly influenced by genetic factors. Our positional cloning studies of the progressive ankylosis (ank) gene in mice has identified a novel genetic pathway that normally protects joints and articular cartilage from mineralization and joint disease (Ho et al. 2000) . The ank gene encodes a novel, multiple-pass transmembrane protein that stimulates the transport of a small-molecule inhibitor of mineral deposition. The same inhibitor is also used in tartar-control toothpaste to prevent deposition of mineral and calcium deposits along the gum line. Defects in ank remove this "tartar-control" principal from the joints, leading to ectopic mineral deposition in and around joints, and development of arthritis.

We have found mutations in the human ANK gene that also cause ectopic crystal formation and joint disease (Pendleton et al. 2002). Other groups have found unusual ANK mutations that cause excess bone formation in the skull, with little effect on joints (craniometaphysial dsyplasia). We are investigating how different types of mutations in the ANK gene lead to different molecular, cellular, and clinical phenotypes, and how manipulation of ANK expression and activity may modify susceptibility to arthritis and joint disease (Nociti et al. 2002; Gurley et al. 2006) .

Our positional cloning studies of the mouse brachypodism gene also identified a key BMP signaling molecule (Growth Differentiation Factor 5, GDF5) that has turned out to play a key role in both joint formation and the very most common forms of arthritis in humans (Storm et al. 1994). GDF5 is expressed in a dramatic series of stripes across developing skeletal precursors, corresponding to the inter zone regions where synovial joints form between bones in the limbs (Storm et al. 1996). The mutant phenotypes in brachypodism mice suggest that the gene is required both for skeletal growth and for normal joint formation, and GDF5 has since become one of the most commonly used markers for joint formation and patterning.

The GDF5 gene has also been prominently highlighted by three very different types of human studies: 1) Genetic variants in the GDF5 region were among the first associated with human height variation (Sanna et al. 2008 Nat Genet); 2) GDF5 variants are among the best replicated risk factors for extremely common forms of human osteoarthritis (Miyamoto et al. 2007 Nat Genet); 3) GDF5 variants show strong signatures of positive evolutionary selection during human migrations out of Africa (Voight et al. 2006 PLoS Biol). In each case, the best-associated DNA changes are found in non-coding regions of the GDF5 gene, suggesting that regulatory changes underlie each of these interesting genetic associations in humans. We have dissected the regulatory elements of the mouse and human GDF5 genes. Our studies have identified a remarkable array of distinct modular enhancers, each controlling joint formation in different anatomical regions of the body (See “Heads, shoulders, elbows, knees, and toes” cover story, Chen et al. 2016). We have also identified a separate GDF5 enhancer that controls bone growth rather than joint formation. This highly conserved growth enhancer shows a single base pair mutation in Neandertals and many modern humans, which reduces the activity of the enhancer and appears to provide the molecular basis for positive selection in human history (Capellini et al. 2017). Interestingly, because of this evolutionary history, a linked “shorter and more arthritis” haplotype of GDF5 is now carried by billions of people around the world. Although the increased risk of arthritis is relatively modest (1.3 to 1.8 fold), the very high prevalence of the selected haplotype accounts for millions of cases of arthritis in modern European and Asian populations. These studies illustrate many interesting principles of evolution in history and medicine, including the reuse of particular variants in archaic and modern humans, the important role of regulatory variation in controlling common morphological traits and diseases, and the way that past selective advantages can sometimes lead to evolutionary tradeoffs that increase the risk of other late-onset disorders in modern populations (Capellini et al. 2017).

More information on research projects in mice, sticklebacks, and human evolution.

Stanford University School of Medicine,  Department of Developmental Biology,  279 Capus Drive,  Beckman Center B300,  Stanford, CA,  94305-5329