LONDON ¿ A rare disorder has once again provided clues to the mechanisms responsible for a common condition that has some similar features. Researchers studying Papillon-Lefevre syndrome (PLS), which affects about one in 4 million people, say their work will help elucidate the causes of common gum disorders that often lead to the loss of teeth.

The main characteristics of PLS are apparently unrelated. Sufferers have severe periodontitis affecting both the milk teeth and the adult teeth, which results in premature tooth loss. They also have a condition called palmoplantar keratosis. This affects the skin on the hands, which may vary from mildly scaly to greatly thickened. The elbows and knees also may be involved.

Nalin Thakkar, senior lecturer in medical genetics and consultant oral pathologist at St Mary¿s Hospital in Manchester, UK, told BioWorld International, ¿Periodontal disease, which is inflammation of the gums, is very common. It affects up to 30 percent of the population and it is the most common cause of tooth loss ¿ not tooth decay, as many people imagine. The health costs of this disease are therefore high, as are the costs of service provision by the health service.¿

Having identified a few families affected by PLS, Thakkar decided that finding the genetic cause of this condition might shed light on the process by which the more common gum disorders occur, as well as suggesting ways of treating and preventing them.

Working with collaborators in Manchester, Leeds and Belfast ¿ as well as Westmead, Australia, and Cairo, Egypt ¿ Thakkar and his colleagues found that the mutation responsible for PLS caused loss of activity of a protease called cathepsin C. Their results are reported in a paper in the December Nature Genetics titled, ¿Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis.¿

Thakkar explained that six of the eight families the group worked with, who were affected by PLS, were consanguineous ¿ that is, the parents were related. Three of these families were Egyptian and three were Indian/Pakis tani. The remaining two families were Lebanese and the parents were not known to be consanguineous but in fact were, as revealed by the genetic studies.

Thakkar told BioWorld International, ¿We knew the gene for PLS had been mapped to chromosome 11, so we set about narrowing down the region by looking for areas where identical regions had been inherited from the father and from the mother.¿ This strategy led the group to a region where several genes were known to be encoded.

One of them was CTSC, the gene encoding the lysosomal protease cathepsin C. ¿This was a very strong candidate gene because it was known to be involved in the lysosomal function of polymorphonuclear leukocytes, which are a type of white cell also known as polymorphs. If you look at other inherited conditions where you get periodontal disease, many of them are associated with polymorph dysfunction, too,¿ Thakkar said.

The next step was to look for mutations in the gene. After a few months¿ delay, during which the team discovered that the previously reported structure of the gene was wrong, Thakkar and his colleagues identified mutations in all the affected individuals. None of these mutations was present in 200 ethnically matched controls.

However, because some of the observed mutations resulted in only a single amino acid change in the protein, Thakkar decided to carry out tests to determine the function of cathepsin C in affected and non-affected individuals.

He said, ¿We found that in affected homozygotes, the function of cathepsin C was completely abolished, and parents who were carriers had 50 percent of the activity, which is exactly what you would expect. That clinched it for us.¿

So how does loss of cathepsin C activity account for the symptoms of PLS? As mentioned, one important role of cathepsin C is to activate bactericidal enzymes in polymorphs ¿ and these cells are involved at the front line in the fight against plaque bacteria. Cathepsin C is also known to activate granzyme A and granzyme B, two molecules produced by cytotoxic T cells and natural killer cells, and used by these cells in the killing of other cells that have been, for example, compromised by infection. It is not clear whether either or both of these mechanisms is important in the defense against plaque bacteria.

In addition, while no one has studied the role of cathepsin C in epithelium, Thakkar said, ¿We can speculate that it could be involved in the differentiation of cells or in the shedding of cells. It is a protease and might be involved in allowing cells to shed ¿ if you cannot do that, then you might build up a thickened layer of skin.¿

In the gums, he added, loss of cathepsin could theoretically affect the junctional epithelium which binds the gum to the tooth, as well as reducing antibacterial defenses by polymorphs against bacteria which enter the gums.

The group is now examining what role cathepsin C plays in the epithelium, and how loss of this protease affects the way in which polymorphs deal with plaque bacteria. Another line of inquiry is whether the activity of cathepsin C varies among the 10 percent to 20 percent of people who have early-onset periodontitis. Thakkar suggested it is possible that they may be homozygous for certain polymorphisms in the CTSC gene that severely reduce the enzyme¿s activity.

Thakkar concluded: ¿If we can identify patients who are at higher risk of periodontitis, then we may be able to target preventative measures to these patients, thus helping them to retain their teeth. It is also possible that by fully understanding how the body deals with the plaque bacteria we may be able to devise new treatments that help prevent or treat this common disease.¿