Peutz-Jeghers Disease Gene Identified: Enzyme Loss Causes Polyps ...( ry California constructed a conti...)

ry, 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
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Contact: Dieter Jenne
djenne@alf.biochem.mpg.de
+49-89-8578-3588
Max-Planck-Gesellschaft
1-Jan-1998

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