Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033036 (APC)
 10,214 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Screening of fetal brain and fetal retina complementary DNA (cDNA) libraries and exon-connection experiments using brain cDNA have identified three exons 5' to exon 1 of the adenomatous polyposis coli gene. The exons are termed (from 5'-3') 0.3, 0.1, and 0.2; exons 0.1 and 0.2 are contiguous genomically. Library screening revealed alternatively spliced cDNAs containing the following combinations of 5'-exons: 0.3 + 1 + 2, 0.3 + 2, 0.1 + 0.2 + 1 + 2, and 0.1 + 1 + 2. Exon-connection experiments also identified these four forms in mRNAs from tissues and cultured cell lines, along with two additional forms, 0.1 + 0.2 + 2 and 0.1 + 2. The multiple splice forms may lead to proteins of differing activity; for example, products derived from cDNAs without exon 1 will lack most of a heptad-repeat domain that supports formation of homodimers. No mRNA species combining 0.3 with either 0.1 or 0.2 were identified. The existence of two apparently separate 5'-ends of APC suggests the possibility of two independent promoters. The genomic sequence adjacent to exon 0.3 confers promotor activity when cloned in a chloramphenicol acetyltransferase expression vector and transfected into a colon cancer cell line.
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PMID:Demonstration of promoter activity and alternative splicing in the region 5' to exon 1 of the APC gene. 818 87

Mutations in the APC gene are responsible for the dominantly inherited colon cancer syndrome, familial adenomatous polyposis (FAP). We have designed PCR primers which allow amplification by RT-PCR of exons 1-14 of the APC gene in six overlapping segments. The amplicons have been screened for the presence of mutations in patients affected with FAP using heteroduplex analysis. One patient has been identified with an alternatively spliced transcript involving exon 14 and a single base insertion mutation within the same exon.
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PMID:Mutation detection in exons 1-14 of the adenomatous polyposis coli gene: identification of an alternatively spliced transcript. 891 Aug 93

A family is presented with attenuated familial adenomatous polyposis of variable phenotype. The clinical features range from sparse right-sided polyposis and cancer in the proximal colon at the age of 34 to pan-colonic polyposis and cancer at the age of 68. Rectal sparing is common to all affected members. Heteroduplex analysis detected bands of altered mobility in exon 9 of the APC gene in all affected family members. Subsequently, a frameshift mutation was found in the alternatively spliced region of exon 9 at codon 398 which resulted in a stop signal 4 codons downstream. Alternatively spliced transcripts that delete the mutation were readily amplified from normal colonic mucosa and therefore create a mechanism for the attenuated phenotype seen in this family.
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PMID:A family with attenuated familial adenomatous polyposis due to a mutation in the alternatively spliced region of APC exon 9. 960 37

The human homologue of Drosophila tumor suppressor dlg, hDLG1, is one of the proteins known to interact with APC, a tumor suppressor for colorectal cancer. Alternative splicing of this gene generates transcripts either with [insertion 1 (I1)] or without 99 nucleotides in the 5' part of the dlg homology repeats (DHR) domain. We found almost equivalent expression of these two splicing variants in most human tissues; however, in skeletal muscle the transcript with the 99-bp insertion was predominant, and in the brain, that without the 99-bp insertion was expressed predominantly. We also examined alternative splicing in the region between the SH3 and GUK domains where two different sizes of insertions, 34 nucleotides (I2) or 100 nucleotides (I3), had been reported, and found various splicing patterns among the tissues examined. In brain we detected six different, alternatively spliced transcripts, two of which included a novel, 36-bp, brain-specific exon encoding a peptide bearing significant homology to a portion of rat synapse-associated protein, SAP97/PSD95. Subsequently, we investigated the splicing patterns of the hDLG1 gene in 24 neuroblastoma cell lines. In two-thirds of these lines, the splicing patterns were altered from those observed in normal brain tissue. As one-third retained the normal brain-splicing pattern, the loss of normal splicing of hDLG1 may not in itself cause formation of tumors, but it might reflect the biological character of individual neuroblastomas.
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PMID:Identification of brain-specific splicing variants of the hDLG1 gene and altered splicing in neuroblastoma cell lines. 962 17

Several human malignancies frequently exhibit deletions or rearrangements of the distal short arm of chromosome 1 (1p36), and a number of genetic diseases also map to this region. The carbonic anhydrase (CA6) and alpha-enolase (ENO1) genes, previously mapped to 1p36, were physically linked in yeast- and P1-artificial chromosome (YAC and PAC) contigs. PACs from the contig were mapped to 1p36.2 by fluorescence in situ hybridization. The ESTs D1S2068, D1S274E, D1S3275, and stSG4370 were also placed in the same contig. The physical map was integrated with the genetic map of chromosome 1 by assignment of genetic markers D1S160, D1S1615, and D1S503 to the contig. Sequencing of the EST clone representing D1S274E indicated that it was derived from the same transcript as D1S2068E and corresponded to the SLC2A5 (GLUT5) gene, previously assigned to 1p31. Reassignment of SLC2A5 to 1p36.2 was confirmed by somatic cell and radiation hybrid mapping panels and was consistent with previous EST mapping data. Sequencing of the EST clone for D1S274E revealed the presence of intronic sequences, suggesting that the clone was derived from an unprocessed message. The presence of unprocessed and/or alternatively spliced EST clones has potential ramifications for EST-based genomic projects. This information should facilitate the mapping of tumor suppressor and genetic disease loci that have been localized to this region.
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PMID:Physical mapping of the CA6, ENO1, and SLC2A5 (GLUT5) genes and reassignment of SLC2A5 to 1p36.2. 969 Nov 77

The t(8;13)(p11;q12) is the most common translocation associated with the 8p11 myeloproliferative syndrome and results in an identical mRNA fusion between ZNF198 at 13q12 and FGFR1 at 8p11 in all cases thus far reported. ZNF198 is a widely expressed gene that is predicted to encode a 1377-amino-acid protein with five Zn finger-related motifs known as MYM domains. To determine the genomic DNA structure of ZNF198, we employed bubble PCR from PAC clones with a panel of gene-specific primers. Sequencing of these products revealed that ZNF198 consists of 26 exons with the initiation codon located in exon 4. The t(8;13) results in a consistent mRNA fusion of ZNF198 exon 17 to FGFR1 exon 9. Notable features of the structure of ZNF198 include three noncanonical GC donor splice sites and the presence of an alternatively spliced intron within exon 4. Amplification of genomic DNA from six t(8;13) patients with primers to ZNF198 exon 17 and FGFR1 exon 9 yielded patient-specific products ranging in size from 500 bp to 2.5 kb, indicating that the positions of the breakpoints in the t(8;13) are tightly clustered. The positions of the six t(8;13) breakpoints were determined and found to be distributed across ZNF198 intron 17 and FGFR1 intron 8 with no apparent subclustering. No consistent sequence motifs, repeats, or topoisomerase II cleavage sites were found at or near the breakpoints. It remains unclear why the t(8;13) translocation breakpoints occur within such small genomic regions, and it is possible that strict ZNF198-FGFR1 coding requirements restrict the positions of the breakpoints.
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PMID:The genomic structure of ZNF198 and location of breakpoints in the t(8;13) myeloproliferative syndrome. 988 6

CD1d is a critical molecule for the presentation of lipid antigens to natural killer (NK) T cells. To investigate the molecular complexity of CD1d, alternatively spliced transcripts in peripheral blood mononuclear cells from three healthy subjects were analyzed by PCR and sequencing methods. We found eight alternatively spliced variants of the CD1D gene (V1-V8), seven of which are newly established variants (V2-V8). V1 and V4 are in-frame; however, the other six variants (V2, V3, V5-V8) are out-of-frame. V1, V2, V4, and V5 lack a beta(2)-microglobulin binding site (alpha3 domain), indicating the unstable presentation of the CD1d molecule on the surface. In V2 and V5, the transmembrane region is absent, supporting a soluble CD1d. In the V3-V8 variants, the antigen binding region (alpha1 and alpha2 domains) is partially defective, suggesting incomplete functional products. In contrast, the V1 and V2 transcripts bear the complete antigen binding site, resulting in functional proteins. Especially, the V2 splicing variant might function as an inhibitory soluble CD1d molecule and regulate the presentation of antigens on APC to NKT cells.
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PMID:Alternative splicing forms of the human CD1D gene in mononuclear cells. 1100 91

The MAPRE genes encode the EB1 family proteins. The yeast EB1 protein had been shown to play important roles in microtubule dynamic regulation, cytokinesis, mitotic spindle positioning, and episome segregation. To facilitate functional studies of mammalian EB1 family proteins, we characterized the human MAPRE genes (MAPRE1, MAPRE2, and MAPRE3) and their proteins (EB1, RP1, and EBF3). We found that the three MAPRE genes had similar genomic structures but were on different chromosomes. We showed that EB1 family proteins appeared to be expressed ubiquitously. We identified two EBF3 proteins, which were encoded by alternatively spliced MAPRE3 mRNAs. We demonstrated that there were also two RP1 proteins, which were products of translation from different initiation codons. We showed that the three EB1 family proteins had different abilities to interact with APC in vitro, and we provided the first direct evidence for the association between endogenous EB1 and APC.
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PMID:Characterization of human MAPRE genes and their proteins. 1116 7

Familial Adenomatous Polyposis (FAP) is an autosomal dominant heritable disorder caused by germ-line mutations in the APC gene. To date, more than 300 germ-line mutations within this gene have been described. Using PCR, SSCP and DNA sequencing, we have identified a new mutation in the alternatively spliced region of exon 9 (1042C-->T), which results in a stop signal. This mutation manifested an aggressive form of FAP with onset of symptoms in one proband at age 17. Our results differ from reported exon 9 mutations in the spliced-out portion of the gene manifesting an attentuated form of FAP (AAPC) [Varesco et al 1994; van der Luijt et al. 1995; Curia et al. 1998; Young et al. 1998]. When analyzing this family, we encountered a mutant FAP gene which had undergone a second mutational event, a deletion. In addition to linkage analysis, both the occurrence of the two exon 9 mutation-carrier siblings, of which one is affected, harboring the same novel deletion in one generation of this family, and its absence in both parents indicates the existence of maternal germ-line mosaicism for cells bearing the latter second mutational event. Our study is only the second report of parental mosaicism in the APC gene.
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PMID:Maternal mosaicism for a second mutational event--a novel deletion--in a familial adenomatous polyposis family harboring a new germ-line mutation in the alternatively spliced-exon 9 region of APC. 1175 14

Germline mutations of the adenomatous polyposis coli ( APC) gene cause familial adenomatous polyposis (FAP), an autosomal, dominantly inherited disease that predisposes patients to colorectal cancer. The APC gene is composed of 15 coding exons and encodes an open reading frame of 8.5 kb. The 3' 6.5 kb of the APCopen reading frame is encoded by a single exon, exon 15. Most identified APC mutations are at the 5' half of the APC open reading frame and are nucleotide substitutions and small deletions or insertions that result in truncation of the APC protein. Very few well-characterized gross alterations of APC have been reported. Patients with FAP typically develop hundreds to thousands of colorectal tumors beginning in their adolescence. A subgroup of patients with FAP who develop fewer tumors at an older age have what is called attenuated FAP (AFAP). Accumulating evidence indicates that patients carrying germline APC mutations in the first four coding exons, in the alternatively spliced region of exon 9, or in the 3' half of the coding region usually develop AFAP. We characterized two germline APC alterations that deleted the entire APC exon 15 as the result of 56-kb and 73-kb deletions at the APC locus. A surprising finding was that one proband had the typical FAP phenotype, whereas the other had a phenotype consistent with that of AFAP.
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PMID:Different familial adenomatous polyposis phenotypes resulting from deletions of the entire APC exon 15. 1213 40


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