Oral Diseases (2000) 6, 263 2000 Macmillan Publishers Ltd All rights reserved 1354-523X/00 $15.00

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GUEST EDITORIAL

Genetic analysis of Papillon-Lefevre syndrome

N Thakker

Department of Oral Pathology, University Dental Hospital of Manchester, Higher Cambridge Street, Manchester M15 6FH, UK

One of the less obvious ways in which genetic research canadvance medicine is by using rare inherited conditions toshed light on the pathology of common diseases that lackany simple pattern of inheritance. Colorectal cancer was theclassic example of this (Kinzler and Vogelstein, 1996), butnow maybe dentistry will have its turn. Papillon-Lefe`vresyndrome (PLS) is an exceedingly rare autosomal recessivedisease presenting a variable picture of severe periodontaldisease and palmoplantar keratoderma (Gorlinet al, 1964).Can genetic study of PLS help us understand ordinary per-iodontal disease?

For successful genetic analysis, the key is not a highincidence but a simple pattern of inheritance. Common dis-eases with a familial tendency but no simple pattern ofinheritance, like multiple sclerosis or type 2 diabetes, areproving exceedingly refractory to genetic analysis, whereasthe genes underlying all manner of excessively rare Men-delian diseases have been identified. Given a few familieswith the unambiguous pedigree of a single gene disease, itis usually possible to define the chromosomal location ofthe gene. In the old days one then embarked on the fear-some labour of positional cloning, trying to find anunknown gene hidden somewhere among several millionbase pairs of DNA. Nowadays it is all much simpler. Havingidentified your chromosomal region, you go to one of thedatabases containing the fruits of the Human Genome Pro-ject, download a list of genes at that location, and select acandidate on the basis of its expression pattern or resem-blance to known disease genes. Then you go back to thedatabase, download the DNA sequence of your gene, designprimers to amplify that sequence in the polymerase chainreaction (PCR), and use them to make enough copies of thegene from your patient’s DNA to screen for mutations.

Papillon-Lefevre syndrome was mapped in this way,through the efforts of several groups, to a small region ofchromosome 11. Following the New Genetics paradigm,we checked genes in that region. Cathepsin C caught ourattention because it degrades proteins. Lysosomal dysfunc-tion and conditions like Chediak-Higashi syndrome canresult in severe periodontal disease—could this be a hint?At that point we met an instructive example of the gapbetween theory and reality. We downloaded the DNA

Correspondence: Dr Nalin Thakker, Department of Oral Pathology, Uni-versity Dental Hospital of Manchester, Higher Cambridge Street, Manch-ester M15 6FH, UK. Tel:+44 0161 275 6720, Fax:+44 0161 6840/6797

sequence (Genbank entry U79415), designed PCRprimers—and they wouldn’t work. For weeks and monthswe tried every trick we knew to amplify the U79415sequence, and just couldn’t. Eventually we bit the bulletand went back to old-fashioned positional cloning habits.We isolated a clone containing the cathepsin C gene,sequenced it—and discovered that the Genbank entry hasthe structure of the gene badly wrong. The databases arewonderful tools, but are not perfect and must be used withcaution. Armed with the correct sequence, we quicklyfound our mutations (Toomeset al, 1999).

Papillon-Lefevre syndrome is caused by completeabsence of cathepsin C activity. Is the more common per-iodontitis caused by partial loss of function? We are check-ing, but probably not. The parents of PLS children, whohave only 50% of normal cathepsin C activity, do not seemto have any periodontal problems. Probably we will get theinsight by stepping back a bit. What PLS does tell us isthat the pathway involving cathepsin C is vital to periodontalhealth. The role of cathepsin C in maintaining the balancebetween the oral microflora and the immune system is cer-tain, but knowing the cause of PLS will tell us where tolook. In that connection, the paper in the current issue (Nittaet al, pp 278–281) looking at HLA types in PLS is prophetic.True, it has been upstaged by our cathepsin work, and wenow know HLA is not the primary determinant of PLS. Butwe also suspect that looking at immune function is the wayto understand both PLS and common periodontal disease.How lack of cathepsin C causes palmoplantar keratodermais, however, another story and still a mystery. Watch thisspace.

Nalin ThakkerDepartments of Genetics and Oral Pathology

University of Manchester

References

Gorlin RJ, Sedano H, Anderson VE (1964). The syndrome ofpalmar-plantar hyperkeratosis and premature periodontaldestruction of teeth.Pediatrics65: 895–908.

Kinzler KW, Vogelstein B (1966). Lessons from hereditary col-orectal cancer.Cell 87: 159–170.

Toomes C, James J, Wood AJ, Wu CL, McCormick D, Lench Net al (1999). Loss of function mutations in cathepsin C resultin periodontal disease and palmoplantar keratosis (Papillon-Lefevre syndrome).Nat Genet23: 421–424.