Peutz-Jeghers Syndrome: Confirmation of Linkage to Chromosome 19p13.3 and Identification of a Potential Second Locus, on 19q13.4

Abstract

Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease with variable expression and incomplete penetrance, characterized by mucocutaneous pigmentation and hamartomatous polyposis. Patients with PJS have increased frequency of gastrointestinal and extraintestinal malignancies (ovaries, testes, and breast). In order to map the locus (or loci) associated with PJS, we performed a genomewide linkage analysis, using DNA polymorphisms in six families (two from Spain, two from India, one from the United States, and one from Portugal) comprising a total of 93 individuals, including 39 affected and 48 unaffected individuals and 6 individuals with unknown status. During this study, localization of a PJS gene to 19p13.3 (around marker D19S886) had been reported elsewhere. For our families, marker D19S886 yielded a maximum LOD score of 4.74 at a recombination fraction (theta) of .045; multipoint linkage analysis resulted in a LOD score of 7.51 for the interval between D19S886 and 19 pter. However, markers on 19q13.4 also showed significant evidence for linkage. For example, D19S880 resulted in a maximum LOD score of 3.8 at theta = .13. Most of this positive linkage was contributed by a single family, PJS07. These results confirm the mapping of a common PJS locus on 19p13.3 but also suggest the existence, in a minority of families, of a potential second PJS locus, on 19q13.4. Positional cloning and characterization of the PJS mutations will clarify the genetics of the syndrome and the implication of the gene(s) in the predisposition to neoplasias.

Clinicopathologic and Molecular Features of Pancreatic Adenocarcinoma Associated with Peutz-Jeghers Syndrome

“…First, inactivating mutations that either truncate or disrupt the kinase activity of the protein encoded by this gene are detected in the majority but not all cases of PJS. [6][7][8][60][61][62][63][64][65][66][67][68][69] Second, dominant inheritance of a mutant STK11/LKB1 allele coupled with LOH or somatic mutation of the remaining wild-type STK11/LKB1 allele has been documented in PJS patients with various malignancies. 10,11,[70][71][72][73] Third, inactivating STK11/LKB1 mutations or altered STK11/LKB1 expression have also been identified in various sporadic cancers.…”

Genetics of Carney complex and related familial lentiginoses, and other multiple tumor syndromes

“…patients with the syndrome, the normal allele of STK11/LKB1 was lost (104,105).Genetic heterogeneity, like in Carney complex, is possible in PJS; in ours and other laboratories, kindreds with this syndrome have been found that either do not link to the reported locus or do not have STK11/LKB1 mutations (106,107). Another locus for PJS has been proposed on the long arm of chromosome 19 (19q13) (106).…”

Polipose nasossinusal em criança com síndrome de Peutz-Jeghers

“…O gen de susceptibilidade da SPJ codificado por STK11 (expressa em serino/theorinine quinase, também chamado LKB1), foi identificado em famílias com a síndrome. Resultados confirmam o mapeamento do locus comum no 19p13.3 mas também sugere a existência na minoria das famílias de um locus potencial, no 19q13.4 13 .…”

“…Os avanços das pesquisas genéticas permitiram a identificação dos gens envolvidos nas mutações cromossômicas responsáveis pela malignização dos pólipos e melanose 13,14,15 .…”