Genetic dieseases: Do your joints scale up?

Ho, A. M., Johnson, M. D. & Kingsley

Around half of elderly people are afflicted by one of the many forms of human arthritis, but the hereditary component of this disease remains poorly understood. A recently reported gene that causes arthritis in mice may reveal what keeps joints scale-free.

The pathogenic aspect of arthritis, in humans as in mice, is often associated with the deposition of crystallised minerals between bones, leading to deterioration of the cartilage that normally cushions either end of a joint. In mice homozygous for a mutation in the ‘progressive ankylosis’ (ank) gene the bones progressively fuse — the animals’ joints gradually stiffen and immobilize by the age of six months.

In the 14 July issue of Science, researchers from Stanford University report the cloning and characterization of the ank gene, using rescue of the ank mouse phenotype with genomic BAC clones. Of the 11 predicted genes in the rescuing 150 Mb clone, only one point mutation was found: a G to T substitution that introduces a premature stop codon in the open reading frame of the ank locus.

The ANK protein is expressed in cartilage cells, where it spans the outer membrane and shuttles pyrophosphate (PPi) in and out of cells. PPi and its derivatives are potent inhibitors of mineral deposition (and are also approved ingredients in tartar-control toothpaste). So, when ank is mutated in mice, the low dose of PPi outside cartilage cells allows more minerals to calcify between joints and new bone to fill in the space where the synovial fluid should be.

The ank gene is found in zebrafish, rats, mice, cows and humans (where ANK is 98% identical to the mouse gene) but not in flies — hardly surprising, as invertebrates have a shell and not a skeleton. So, is ANK involved in hereditary forms of arthritis in humans? This remains to be seen.

Original research paper
Ho, A. M., Johnson, M. D. & Kingsley,
D. M. Role of the mouse ank gene in control of tissue calcification and arthritis. Science 289, 265Ð270 (2000).

Further reading
Sweet, H. O. & Green, M. C. Progressive ankylosis, a new skeletal mutation in the mouse. J. Hered. 72, 87Ð93 (1981).

Reprinted, with permission, from Nature Reviews Genetics. For the original article, with web links, see: http://www.nature.com/nrg/.