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1.
A G Marneros H Mehenni E Reichenberger S E Antonarakis T Krieg B R Olsen 《Cytogenetics and cell genetics》2001,92(3-4):213-216
Mutations in the serine/threonine kinase STK11 lead to Peutz-Jeghers syndrome (PJS) in a subset of affected individuals. Significant evidence for linkage to a second potential PJS disease locus on 19q13.4 has previously been described in one PJS family (PJS07). In the current study, we investigated this second locus for PJS gene candidates. We mapped the main candidate gene in this region, the gene for the transmembrane-type protein tyrosine phosphatase H (PTPRH), within 15 kb telomeric to the marker D19S880. We determined its genomic structure, and performed mutation analysis of all exons and the exon-intron junctions of the PTPRH gene in the PJS07 family. No disease causing mutation was identified in PTPRH in affected individuals, suggesting the existence of an as yet not identified gene on 19q13.4 as a second PJS gene. 相似文献
2.
Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity. 总被引:12,自引:0,他引:12
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H Mehenni C Gehrig J Nezu A Oku M Shimane C Rossier N Guex J L Blouin H S Scott S E Antonarakis 《American journal of human genetics》1998,63(6):1641-1650
Peutz-Jeghers syndrome (PJS) is an autosomal dominant disease characterized by mucocutaneous pigmentation and hamartomatous polyps. There is an increased risk of benign and malignant tumors in the gastrointestinal tract and in extraintestinal tissues. One PJS locus has been mapped to chromosome 19p13.3; a second locus is suspected on chromosome 19q13.4 in a minority of families. The PJS gene on 19p13.3 has recently been cloned, and it encodes the serine/threonine kinase LKB1. The gene, which is ubiquitously expressed, is composed of 10 exons spanning 23 kb. Several LKB1 mutations have been reported in heterozygosity in PJS patients. In this study, we screened for LKB1 mutations in nine PJS families of American, Spanish, Portuguese, French, Turkish, and Indian origin and detected seven novel mutations. These included two frameshift mutations, one four-amino-acid deletion, two amino-acid substitutions, and two splicing errors. Expression of mutant LKB1 proteins (K78I, D176N, W308C, and L67P) and assessment of their autophosphorylation activity revealed a loss of the kinase activity in all of these mutants. These results provide direct evidence that the elimination of the kinase activity of LKB1 is probably responsible for the development of the PJS phenotypes. In two Indian families, we failed to detect any LKB1 mutation; in one of these families, we previously had detected linkage to markers on 19q13.3-4, which suggests locus heterogeneity of PJS. The elucidation of the molecular etiology of PJS and the positional cloning of the second potential PJS gene will further elucidate the involvement of kinases/phosphatases in the development of cancer-predisposing syndromes. 相似文献
3.
黑斑息肉综合征(Peutz-Jeghers syndrome,PJS)是一种以皮肤黏膜色素沉着斑、胃肠道多发息肉、家族遗传性为主要特点的常染色体显性遗传病,随着息肉体积增大,患者年龄增加,消化系统及生殖系统等恶性肿瘤发病率明显增加,主要致病基因为19号染色体短臂上的LKB1/STK11(丝氨酸/苏氨酸激酶)基因,是一种肿瘤易感综合征,临床应及早处理胃肠道息肉及密切随访观察,预防恶性肿瘤的发生及早期诊治,减少PJS带来的危害。 相似文献
4.
曹强坚李威 《现代生物医学进展》2011,11(11):2190-2193
黑斑息肉综合征(Peutz-Jeghers syndrome,PJS)是一种以皮肤黏膜色素沉着斑、胃肠道多发息肉、家族遗传性为主要特点的常染色体显性遗传病,随着息肉体积增大,患者年龄增加,消化系统及生殖系统等恶性肿瘤发病率明显增加,主要致病基因为19号染色体短臂上的LKB1/STK11(丝氨酸/苏氨酸激酶)基因,是一种肿瘤易感综合征,临床应及早处理胃肠道息肉及密切随访观察,预防恶性肿瘤的发生及早期诊治,减少PJS带来的危害。 相似文献
5.
Peutz-Jeghers Syndrome: Confirmation of Linkage to Chromosome 19p13.3 and Identification of a Potential Second Locus, on 19q13.4 总被引:8,自引:0,他引:8
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Hamid Mehenni Jean-Louis Blouin Uppala Radhakrishna Shiv Shanker Bhardwaj Kamla Bhardwaj V.B. Dixit Kent F. Richards Ambrosio Bermejo-Fenoll Antonio Silva Leal Ranjan C. Raval Stylianos E. Antonarakis 《American journal of human genetics》1997,61(6):1327-1334
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. 相似文献
6.
肝激酶B1(liver kinase B1,LKB1),又名丝氨酸/苏氨酸蛋白激酶11(STK11),是一种蛋白激酶,可磷酸化AMP激活的蛋白激酶和12种其他AMPK相关激酶。LKB1还是一种肿瘤抑制蛋白,生殖细胞LKB1基因突变可引发家族性黑斑息肉综合征,而体细胞突变可造成多种肿瘤发生。小鼠Lkb1的失活可导致造血干细胞(HSC)静息的丧失、快速的HSC消耗、严重的全血细胞减少和最终的致死。Lkb1缺陷的HSC细胞显示出线粒体缺陷、膜电位减少和细胞ATP耗竭。这些结果说明LKB1是一种HSC内稳态和造血过程中的新调节因子。 相似文献
7.
Kim DW Chung HK Park KC Hwang JH Jo YS Chung J Kalvakolanu DV Resta N Shong M 《Molecular endocrinology (Baltimore, Md.)》2007,21(12):3039-3049
8.
Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia 总被引:1,自引:0,他引:1
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Chen DH Brkanac Z Verlinde CL Tan XJ Bylenok L Nochlin D Matsushita M Lipe H Wolff J Fernandez M Cimino PJ Bird TD Raskind WH 《American journal of human genetics》2003,72(4):839-849
We report a nonepisodic autosomal dominant (AD) spinocerebellar ataxia (SCA) not caused by a nucleotide repeat expansion that is, to our knowledge, the first such SCA. The AD SCAs currently comprise a group of > or =16 genetically distinct neurodegenerative conditions, all characterized by progressive incoordination of gait and limbs and by speech and eye-movement disturbances. Six of the nine SCAs for which the genes are known result from CAG expansions that encode polyglutamine tracts. Noncoding CAG, CTG, and ATTCT expansions are responsible for three other SCAs. Approximately 30% of families with SCA do not have linkage to the known loci. We recently mapped the locus for an AD SCA in a family (AT08) to chromosome 19q13.4-qter. A particularly compelling candidate gene, PRKCG, encodes protein kinase C gamma (PKC gamma), a member of a family of serine/threonine kinases. The entire coding region of PRKCG was sequenced in an affected member of family AT08 and in a group of 39 unrelated patients with ataxia not attributable to trinucleotide expansions. Three different nonconservative missense mutations in highly conserved residues in C1, the cysteine-rich region of the protein, were found in family AT08, another familial case, and a sporadic case. The mutations cosegregated with disease in both families. Structural modeling predicts that two of these amino acid substitutions would severely abrogate the zinc-binding or phorbol ester-binding capabilities of the protein. Immunohistochemical studies on cerebellar tissue from an affected member of family AT08 demonstrated reduced staining for both PKC gamma and ataxin 1 in Purkinje cells, whereas staining for calbindin was preserved. These results strongly support a new mechanism for neuronal cell dysfunction and death in hereditary ataxias and suggest that there may be a common pathway for PKC gamma-related and polyglutamine-related neurodegeneration. 相似文献
9.
Germline mutations of the serine/threonine kinase LKB1 (also known as STK11) lead to Peutz–Jeghers syndrome (PJS) that is
associated with increased incidence of malignant cancers. However, the tumor suppressor function of LKB1 has not been fully
elucidated. We applied yeast two-hybrid screening and identified that a novel WD-repeat protein WDR6 was able to interact
with LKB1. Immunofluorescence staining revealed that WDR6 was localized in cytoplasm, similar to the localization of LKB1.
Expression of LKB1 was able to inhibit colony formation of Hela cells. Interestingly, coexpression of WDR6 with LKB1 enhanced
the inhibitory effect of LKB1 on Hela cell proliferation. Consistently, WDR6 was able to synergize with LKB1 in cell cycle
G1 arrest in Hela cells. Coexpression of WDR6 and LKB1 was able to induce a cyclin-dependent kinase (CDK) inhibitor p27Kip1. Furthermore, the stimulatory effect of LKB1 on p27Kip1 promoter activity was significantly elevated by coexpression with WDR6. Collectively, these results provided initial evidence
that WDR6 is implicated in the cell growth inhibitory pathway of LKB1 via regulation of p27Kip1. 相似文献
10.
11.
Souza J Faucz F Sotomaior V Filho AB Rosenfeld J Raskin S 《Genetics and molecular biology》2011,34(4):557-561
The Peutz-Jeghers syndrome (PJS) is an autosomal-dominant hamartomatous polyposis syndrome characterized by mucocutaneous pigmentation, gastrointestinal polyps and the increased risk of multiple cancers. The causative point mutation in the STK11 gene of most patients accounts for about 30% of the cases of partial and complete gene deletion. This is a report on a girl with PJS features, learning difficulties, dysmorphic features and cardiac malformation, bearing a de novo 1.1 Mb deletion at 19p13.3. This deletion encompasses at least 47 genes, including STK11. This is the first report on 19p13.3 deletion associated with a PJS phenotype, as well as other atypical manifestations, thereby implying a new contiguous gene syndrome. 相似文献
12.
K Hayashi H Igarashi M Ogawa N Sakaguchi 《Biochemical and biophysical research communications》1999,264(2):449-456
We isolated a murine STK2 (mSTK2) cDNA that is homologous to murine Nek1 serine/threonine kinase, a family member related to the cell cycle regulator kinase NIMA of Aspergillus nidulans. Structural comparison demonstrated that the kinase domain of mSTK2 is highly similar to NIMA/Nek family but the C-terminal region is not similar to any proteins except for human STK2 (hSTK2). Similarly to Nek1, mSTK2 is expressed ubiquitously among various organs and is upregulated in the testis. The expression and localization of mSTK2 are not associated with the cell cycle progression of mitogen-activated lymphocyte and DNA-transfected fibroblast. The substrate specificity of mSTK2 is similar to NIMA, but the phosphorylation is observed exclusively upon threonine residues rather than serine. The mSTK2 is shown to be a new member of the NIMA/Nek family with similar substrate specificity, which might participate in a different role from NIMA kinase involved in the cell cycle regulation. 相似文献
13.
M S Davids E Crawford S Weremowicz C C Morton N G Copeland D J Gilbert N A Jenkins M C Phelan M J Comb M B Melnick 《Genomics》2001,77(1-2):2-4
We determined the chromosomal location of the mouse gene Stk25, encoding a member of the Ste20/PAK family of serine/threonine kinases, by interspecific backcross analysis. We mapped Stk25 to the central region of mouse chromosome 1 linked to Chrng (formerly Acrg) and En1. This central region of mouse chromosome 1 shares a region of homology with the long arm of human chromosome 2, suggesting that the human homologue of Stk25 would also map to 2q. We proved this prediction of syntenic homology correct by mapping human STK25 to 2q37. Deletion of the 2q37 region has been implicated in the expression of pseudopseudohypoparathyroidism (PPHP), a disease which shares features of the Albright hereditary osteodystrophy (AHO) phenotype. To investigate a pathogenetic relationship between STK25 and PPHP, we carried out fluorescence in situ hybridization (FISH) using an STK25 gene probe and chromosomes from PPHP patients characterized as having small deletions near the distal end of 2q. PPHP patient DNA showed no hybridization to STK25 genomic DNA, indicating that STK25 is contained within the deleted chromosomal region. This finding, in conjunction with previous studies demonstrating the role of Ste20/PAK kinases in heterotrimeric G protein signaling, suggests that STK25 is a positional candidate gene for PPHP. 相似文献
14.
Setogawa T Shinozaki-Yabana S Masuda T Matsuura K Akiyama T 《Biochemical and biophysical research communications》2006,343(4):1186-1190
The LKB1/STK11 serine/threonine kinase is mutated in Peutz-Jeghers syndrome and various sporadic cancers such as lung adenocarcinoma. We show here that LKB1 forms a complex with LMO4, GATA-6, and Ldb1, and enhances GATA-mediated transactivation in a kinase-dependent manner. We further demonstrate that LKB1 has the potential to induce p21 expression in collaboration with LMO4, GATA-6, and Ldb1 through the p53-independent mechanism. Our findings suggest that LKB1 regulates GATA-mediated gene expression and that this activity of LKB1 may be important for its tumor suppressor function. 相似文献
15.
16.
Stratakis CA 《Hormone research》2000,54(5-6):334-343
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. 相似文献
17.
Hidewaki Nakagawa Kumiko Koyama Yasuo Miyoshi Hiroshi Ando Shozo Baba Masahiro Watatani Masayuki Yasutomi Nariaki Matsuura Morito Monden Y. Nakamura 《Human genetics》1998,103(2):168-172
Peutz-Jeghers Syndrome (PJS) is an autosomal dominant hereditary disease characterized by hamartomatous polyposis involving
the entire bowel. Recently STK11, a gene bearing a mutation responsible for PJS, was isolated. We investigated the entire
coding region of STK11 in 15 unrelated PJS families by the PCR-SSCP (polymerase chain reaction-single strand conformation
polymorphism) method and PCR-direct sequence analysis, and found nine different, novel mutations among ten of those families.
One nonsense mutation and five different frameshift mutations (two families carried the same mutation), all of which would
cause truncation of the gene product, were found in seven families; mutations found in five families were clustered within
exon 6. Among these five mutations, three occurred at the mononucleotide-repeat region (CCCCCC) of codons 279–281, suggesting
that this region is likely to be a mutational hotspot of this gene. One of the remaining three families carried a 3-bp in-frame
deletion that would eliminate an asparagine residue within a kinase domain of the product; the other two carried intronic
mutations at or adjacent to the consensus dinucleotide sequences of splice-acceptor or -donor sites, which were likely to
lead to aberrant splicing.
Received: 9 March 1998 / Accepted: 1 May 1998 相似文献
18.
Kuramochi S Matsuda Y Okamoto M Kitamura F Yonekawa H Karasuyama H 《Immunogenetics》1999,49(5):369-375
LOK is a new and unique member of the STE20 family with serine/threonine kinase activity, and its expression is restricted
mostly to lymphoid cells in mice. We cloned the cDNA encoding the human homologue of LOK. The amino acid sequence deduced
from the cDNA shows a high similarity to that of mouse LOK, with 88% identity as a whole. The kinase domains at the N-terminus
and the coiled-coil regions at the C-terminus are particularly conserved, showing 98% and 93% identity, respectively. Western
blot analysis with mouse LOK-specific antibody detected 130 000 M
r LOK proteins in human and rat lymphoid cell lines and tissues. The gene encoding the LOK (STK10/Stk10) gene was mapped by fluorescence in situ hybridization to chromosome 5q35.1 in human, chromosome 11A4 in mouse, and chromosome
10q12.3 in rat. By virtue of polymorphic CA repeats found in the 3' untranslated region of the mouse Stk10 gene, the Stk10 locus was further pinpointed to chromosome 11 between D11Mit53 and D11Mit84, using the intersubspecific backcross mapping panel. These results established STK10 as a new marker of human chromosome 5 to define the syntenic boundary of human chromosomes 5 and 16 on mouse chromosome 11.
Received: 28 September 1998 / Revised: 2 November 1998 相似文献
19.
Genome-wide scans have mapped economically important quantitative trait loci (QTL) for mastitis susceptibility in dairy cattle at the telomeric end of bovine chromosome 18 (BTA18). In order to increase the density of markers in this chromosomal region and to improve breakpoint resolution in the human-bovine comparative map, this study describes the chromosomal assignment of seven newly developed gene-associated markers and five microsatellites and eight previously mapped sequence tagged site markers near these QTL. The orientation of KCNJ14, BAX, CD37, NKG7, LIM2, PRKCG, TNNT1, MGC2705, RPL28, EPN1, ZNF582, ZIM2, STK13, ZNF132 and SLC27A5 on the 3000-rad radiation hybrid (RH) map of BTA18 is homologous to the organization found on the corresponding 10 Mbp of human chromosome 19q (HSA19q). The resulting bovine RH map with a length of 20.9 cR spans over about 11 cM on the bovine linkage map. The location of KCNJ14 and SLC27A5 flanking the RH map on BTA18q25-26 has been confirmed by fluorescence in situ hybridization. The data of this refined human-bovine comparative map should improve selection of candidate genes for mastitis susceptibility in dairy cattle. 相似文献