Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peutz-Jeghers syndrome (PJS, #175200) and Carney complex (CNC, OMIM#160980) are the two most common multiple neoplasia syndromes associated with lentiginosis. Both disorders are inherited in an autosomal dominant manner and they have recently been elucidated at the molecular level. PJS and CNC share manifestations with Cowden syndrome (or Cowden disease) (CS, OMIM#158350) and Bannayan-Riley-Ruvalcaba syndrome (BRR, OMIM#153480). The endocrine tumors of CS and PJS, which could classify these disorders as variant types of multiple endocrine neoplasias (MENs), are not present in most CS and BRR patients, but lentigines are shared by PJS, CNC and BRR. The serine-threonine kinase STK11 (or LKB1), located on 19p13, is mutated in more than half of all PJS kindreds. The R1alpha subunit of c-AMP-dependent protein kinase A, located on 17q22-24, is mutated in 40% of CNC kindreds. The protein phosphatase PTEN is mutated in most cases of CS and in almost 50% of BRR kindreds, despite significant clinical heterogeneity in these syndromes. The molecular elucidation of the lentiginoses and their related syndromes identifies new pathways of growth control and cellular regulation that are important for endocrine signaling, tumorigenesis, cutaneous function and embryonic development.
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PMID:Genetics of Peutz-Jeghers syndrome, Carney complex and other familial lentiginoses. 1159 29

Germline mutations distributed across the PTEN tumor-suppressor gene have been found to result in a wide spectrum of phenotypic features. Originally shown to be a major susceptibility gene for both Cowden syndrome (CS), which is characterized by multiple hamartomas and an increased risk of breast, thyroid, and endometrial cancers, and Bannayan-Riley-Ruvalcaba syndrome, which is characterized by lipomatosis, macrocephaly, and speckled penis, the PTEN hamartoma tumor syndrome spectrum has broadened to include Proteus syndrome and Proteus-like syndromes. Exon 5, which encodes the core motif, is a hotspot for mutations likely due to the biology of the protein. PTEN is a major lipid 3-phosphatase, which signals down the PI3 kinase/AKT pro-apoptotic pathway. Furthermore, PTEN is a protein phosphatase, with the ability to dephosphorylate both serine and threonine residues. The protein-phosphatase activity has also been shown to regulate various cell-survival pathways, such as the mitogen-activated kinase (MAPK) pathway. Although it is well established that PTEN's lipid-phosphatase activity, via the PI3K/AKT pathway, mediates growth suppression, there is accumulating evidence that the protein-phosphatase/MAPK pathway is equally important in the mediation of growth arrest and other crucial cellular functions.
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PMID:Protean PTEN: form and function. 1187 59

PTEN, encoding a dual phosphatase tumor suppressor, is mutated in 85 and 65% of individuals with Cowden syndrome (CS) and Bannayan-Riley-Ruvalcaba syndrome (BRRS), respectively. Approximately 23 germline mutations in putative splice sites have been published, but resulting downstream outcome data are limited. We determined splicing defects in PTEN in 40 germline PTEN mutation positive cases and 33 mutation negative cases with classic CS, BRRS and CS- or BRRS-like features. Altered splicing was observed in 4/40 mutation positive probands and 2/33 mutation negative probands. We then sought to characterize the transcriptional and biochemical outcomes of the five distinct splice-site mutations, which led to the skipping of exon 3, 4 or 6. Two mutation negative BRRS patients also showed exon 3 skipping, and later, genomic sequencing revealed a mutation deep in intron 2. The splice-site mutations leading to the deletions of exon 3, 4 or 6 resulted in reduced dual phosphatase activities of PTEN. Deletion of exon 4 was associated with severely reduced lipid phosphatase activity, whereas exon 3 skipping resulted in markedly reduced protein phosphatase activity. In addition, exon 3 deleted transcript and protein were stable and localized to the nucleus more efficiently than the wild-type PTEN. In contrast, exon 4 skipping resulted in unstable transcripts and severely truncated unstable PTEN protein lacking its phosphatase domain. We have not only described for the first time, the effect of a deep intronic/branch-site mutation on exon skipping in PTEN but also found that different splice-site mutations resulting in the deletion of different exons lead to distinct outcomes.
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PMID:Different splicing defects lead to differential effects downstream of the lipid and protein phosphatase activities of PTEN. 1601 36