Scientists at the Max-Planck-Institute of Neurobiology in Martinsried and at the University Hospital of Würzburg in collaboration with their clinical colleagues have unravelled the molecular cause of Peutz-Jeghers syndrome. This rare autosomally inherited disease is characterized by gastrointestinal polyps, brown melanin spots around the lips, and a high risk for various tumors. Their data have been published as an article in Nature Genetics on January 1, 1998. Another international team of scientists reported mutations in the same gene in Peutz-Jeghers families in a letter to Nature on January 8, 1998.

Peutz-Jeghers syndrome was first described by Peutz (1921) and Jeghers (1949), but the genetic and biological basis for this unusual combination of symptoms remained a mystery until very recently. The typical dark brown melanin spots on the lips and around the mouth are easily recognized during childhood, but can fade during adolescence. A serious life-threatening feature of this disease are various tumors which can develop in the gastrointestinal tract, pancreas, ovaries, testis, breast and uterus. The growth of benign hamartomatous tissue appears to be the basis for the later development of malignant neoplasms.

Peutz-Jeghers syndrome is inherited in affected families, but can also appear sporadically. The first step to identify the molecular cause was made exactly one year ago when the responsible genetic factor was located on the tip of the short arm of chromosome 19. Affected individuals in several different families all shared the same chromosomal DNA segment around the anonymous DNA marker D19S886. Over the last few years, Dieter Jenne from the Max-Planck-Institute of Neurobiology and Michael Zimmer from the University of Würzburg, in a collaboration with the Lawrence Livermore National Laboratory, California, constructed a continuous physical map of precisely this critical region. They assembled multiple bacterially cloned and partially overlapping DNA fragments and established a high resolution physical map with many landmarks. In this region they identified a multigene family of immune defense proteases and a large number of new genes about which hardly anything was known, except for their partial DNA sequences.

In the Peutz-Jeghers candidate region around the marker D19S886 they identified and located 21 new genes. Computer assisted evaluation of their sequences in comparison to related genes of known function led them to consider two genes as strong candidates for the Peutz-Jeghers disease. Finally, the gene for the serine threonine kinase 11 (STK11) was found to carry nonsense mutations in three familial cases and two sporadic patients with the Peutz-Jeghers syndrome. All these mutations lead to the synthesis of a truncated and inactive protein. The disease manifestations are triggered by the spontaneous loss of the second and only functional copy of this gene in somatic cells. Simultaneously and independently, a second research team headed by Lauri Aaltonen at the University of Helsinki, who had identified the linkage to chromosome 19p13.3, also found defects in the STK11 gene in 11 out of 12 Peutz-Jeghers families.

The STK11 coding region had initially been cloned by Jun-ichi Nezu from Chugai Pharmaceuticals, Japan, as a new member of the large protein kinase family. Protein kinases are cytosolic regulatory enzymes which modify the functional properties of certain cytosolic proteins (substrates) by adding phosphate groups to the side chains of serine, threonine or tyrosine residues. Kinases have highly diverse functions and are implicated in cell cycle regulation, growth control and signal transduction. The molecular mechanism by which STK11 controls cellular differentiation in the gastrointestinal tract and in other organs is currently unknown. The search for physiological STK11 substrates will yield further insights into the complicated intracellular network of molecules that prevents the development of hamartomatous and preneoplastic lesions in various tissues.

The Peutz-Jeghers syndrome can now be diagnosed at the molecular genetic level. Atypical forms of this syndrome without the classical hallmark of pigment spots during the first two decades of life probably exist and can now be identified. A special screening program for individuals with mutations in the STK11 gene is highly recommended to detect early stages of potentially malignant tumors. The ultimate aim in this field of research is to identify drugs that reduce the extent of polyp formation and cancer risk.