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PubMed2005

Recognition of unknown conserved alternatively spliced exons.

The split structure of most mammalian protein-coding genes allows for the potential to produce multiple different mRNA and protein isoforms from a single gene locus through the process of alternative splicing (AS). We propose a computational approach called UNCOVER based on a pair hidden Markov model to discover conserved coding exonic sequences subject to AS that have so far gone undetected. Applying UNCOVER to orthologous introns of known human and mouse genes predicts skipped exons or retained introns present in both species, while discriminating them from conserved noncoding sequences. The accuracy of the model is evaluated on a curated set of genes with known conserved AS events. The prediction of skipped exons in the approximately 1% of the human genome represented by the ENCODE regions leads to more than 50 new exon candidates. Five novel predicted AS exons were validated by RT-PCR and sequencing analysis of 15 introns with strong UNCOVER predictions and lacking EST evidence. These results imply that a considerable number of conserved exonic sequences and associated isoforms are still completely missing from the current annotation of known genes. UNCOVER also identifies a small number of candidates for conserved intron retention.

Journal Article↗

PubMed1999

[Missense mutations of exons 14 and 18 of Wilson's disease gene in Chinese patients]

OBJECTIVE: To investigate the characteristics of mutations of exons 14 and 18 of Wilson's disease (WD) gene in Chinese patients. METHODS: The subjects of study included 60 unrelated normal controls and 44 unrelated WD patients. Genomic DNA was prepared from peripheral blood leukocytes by a salt-out method. Mutations of exons 14 and 18 in these subjects were screened by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and further confirmed by sequencing. RESULTS: One patient was homozygous for Arg1041Pro mutation of exon 14 and another patient was heterozygous for Asn1270Ser mutation of exon 18. CONCLUSION: The mutations of exons 14 and 18 of WD gene in Chinese patients were confirmed by sequencing for the first time in China. Arg1041Pro was identified as a novel missense mutation. In addition, an Asn1270Ser, previously described mutation, was detected in this study. But exons 14 and 18 are not the hot point mutations of WD gene in Chinese patients.

Journal Article↗

PubMed1985

Exons of the human pancreatic polypeptide gene define functional domains of the precursor.

Pancreatic polypeptide is a 36-amino acid peptide which inhibits pancreatic exocrine function. We have previously determined from the nucleotide sequence of a cDNA that pancreatic polypeptide is derived from a 95-amino acid precursor, prepropancreatic polypeptide. Pulse-chase studies have suggested that the precursor is cleaved to produce three peptides: pancreatic polypeptide, an icosapeptide, and a smaller peptide. In the present study, we have used the cloned cDNA as a hybridization probe to isolate the pancreatic polypeptide gene from a human bacteriophage genomic library. The nucleotide sequence of 2.8 kilobases of DNA representing the entire human pancreatic polypeptide gene was determined. The gene contains four exons and three introns. Exon 1 encodes the 5'-untranslated region of the mRNA, exon 2 encodes the signal sequence and the sequence of pancreatic polypeptide, exon 3 encodes the icosapeptide, and exon 4 encodes a carboxyl-terminal heptapeptide and the 3'-untranslated region of the mRNA. By Southern blot analysis, the gene detected in a pancreatic polypeptide-producing islet cell tumor was indistinguishable from that in normal human leukocytes. The structure of the human pancreatic polypeptide gene is consistent with the hypothesis that prepropancreatic polypeptide generates three distinct peptides, each encoded by a separate exon. Increased expression of pancreatic polypeptide in the islet cell tumor does not appear to be correlated with major alterations in pancreatic polypeptide gene structure.

Adenoma, Islet Cell↗

PubMed2026

Clinical outcomes and genomic features of uncommon EGFR exon 19 deletion subtypes in osimertinib-treated non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) exon 19 deletion subtypes may be associated with differential survival outcomes following EGFR-tyrosine kinase inhibitor treatment. However, evidence remains scarce, particularly regarding osimertinib, and the underlying biological mechanisms are poorly understood. We aimed to compare survival outcomes among EGFR exon 19 deletion subtypes in patients with non-small cell lung cancer (NSCLC) treated with osimertinib. METHODS: In this multicenter retrospective study, patients with NSCLC were stratified according to exon 19 deletion subtypes. Whole-exome sequencing data from the American Association for Cancer Research Genomics Evidence Neoplasia Information Exchange registry and Memorial Sloan Kettering Clinicogenomic Harmonized Oncologic Real-World Dataset were analyzed to investigate co-occurring genomic alterations. RESULTS: Overall, 111 patients with advanced EGFR exon 19 deletion-positive NSCLC were analyzed and 86.5% received osimertinib as first-line therapy. Patients with non-E746_A750del (n = 25) had shorter progression-free survival (PFS) than those with E746_A750del (n = 86) (median: 14.3 vs. 20.6 months; p < 0.05). Among non-E746_A750del subtypes, L747_A750delinsP (n = 4) had a particularly poor prognosis, with significantly worse survival than those with E746_A750del (median PFS: 3.5 vs. 20.6 months; p < 0.001, and median overall survival: 11.8 vs. 48.5 months; p < 0.001). In public database analyses, non-E746_A750del had a higher rate of RBM10 co-mutations, whereas L747_A750delinsP was characterized by frequent CDKN2A/B homozygous deletions and MYC amplifications. CONCLUSIONS: Non-E746_A750del was associated with poorer outcomes, with L747_A750delinsP potentially being a high-risk subtype. Differences in co-occurring genomic alterations may contribute to the prognostic heterogeneity among exon 19 deletion subtypes.

Humans↗

PubMed2026

MET Exon 14 Skipping Mutation in NSCLC: From Genomic Discovery to Biomarker-Guided Therapeutic Innovation.

INTRODUCTION: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and the MET exon 14 skipping mutation is a key oncogenic driver, which promotes tumor progression and provides a new direction for precision therapy. METHODS: A systematic search of English-language literature and clinical trial data related to the MET exon 14 skipping mutation from 2020-2025 was performed to summarize the role of the mutation and therapeutic advances. RESULTS: DNA-based next-generation sequencing (NGS), RNA-based NGS, and RT-qPCR were employed as the main detection methods. Preclinical models confirmed that mutations promote tumor progression by activating the RAS/MAPK pathway. Clinical trials have reported objective remission rates (ORR) of 46-68% for first-line treatment with MET inhibitors in NSCLC patients harboring MET exon 14 skipping mutations. DISCUSSION: MET exon 14 skipping mutation as a therapeutic target for NSCLC has made significant progress, and MET inhibitors are more advantageous than chemotherapy and immunotherapy, and have been recommended by national and international guidelines as a first-line treatment option. Additionally, NGS technology has the potential to dynamically monitor tumor evolution and drugresistant mutations, thereby helping to realize precision medicine. CONCLUSION: The MET exon 14 skipping mutation is an important target for the precision treatment of NSCLC, and MET-TKIs have remarkable efficacy but a prominent problem with drug resistance. The construction of a precision medicine system encompassing diagnosis, treatment, and drug resistance management through multi-omics research, technological innovation, and international collaboration is a key direction for improving prognosis.

Humans↗

PubMed2000

Genetic alterations involving exon 3 of the beta-catenin gene do not play a role in adenocarcinomas of the esophagus.

Beta-catenin has been identified as an oncogene. Phosphorylation of sites encoded by exon 3 of the beta-catenin gene facilitates degradation of this protein by the adenomatous polyposis coli (apc) gene product. Mutations in these sites or inactivation of apc lead to stabilization of beta-catenin, which then translocates to the nucleus where it modulates the transcription of genes involved in tumor formation. To explore the role of beta-catenin mutations in adenocarcinomas of the esophagus, we screened for genetic alterations in exon 3 in 69 tumor samples. We detected no mutations in exon 3 by PCR-SSCP analysis nor did we find large interstitial deletions involving exon 3. beta-catenin immunostaining on 54 tumors showed focal nuclear staining in 7 tumors and homogeneous nuclear staining in 3 tumors; in the latter; no mutations in the mutation cluster region of apc were detected. These results show that genetic alterations of exon 3 of the beta-catenin gene do not occur and therefore do not contribute to the pathogenesis of esophageal adenocarcinomas. The abnormal cytoplasmic and nuclear localization of beta-catenin indicates that other mechanisms leading to elevated free beta-catenin in these cancers must be involved.

Adenocarcinoma↗

PubMed1998

Transcript dosage effect in familial adenomatous polyposis: model offered by two kindreds with exon 9 APC gene mutations.

Analysis of genotype-phenotype correlations in familial adenomatous polyposis (FAP) patients demonstrated that the phenotypic heterogeneity of FAP is partly related to the mutation site. We investigated the molecular basis for the difference in severity of colorectal disease observed comparing FAP patients from two kindreds with neighbouring germline mutations in exon 9 of the APC gene. Patients from one kindred presented with a attenuated form of FAP, characterized by a low number of colorectal adenomas (up to 22). In FAP patients from this kindred, the APC gene mutation was localized at codon 367, in the portion of exon 9 that is alternately spliced. This is expected to result in the splicing-out of the mutation site in a fraction of mRNA molecules and in the residual production of wild-type transcripts from the mutant APC allele. Patients from the other kindred manifested a FAP phenotype characterized by hundreds of colorectal adenomas (320 to > 500). In these patients, the APC gene mutation abolished the donor site of exon 9a, used in both alternately spliced isoforms of the exon. The analysis of the relative levels of mutant and wild-type transcripts in unaffected colonic mucosa demonstrated that the mutant allele was not expressed. The model offered by our FAP patients with neighbouring exon 9 APC mutations supports the view that in addition to the mutation site, the type of mutation and transcript dosage effects contribute to the heterogeneity of disease phenotypes.

Adenomatous Polyposis Coli↗

PubMed1997

Differential splicing of exon 5 of the Wilms tumour (WTI) gene.

The WTI gene encodes a developmentally regulated transcription factor whose function is altered by alternative splicing at two sites: the 17 amino acids of exon 5, whose functional effects are ill-defined, and the 3 amino acids (KTS) between exons 9 and 10, which determine sequence-specific DNA binding and nuclear localisation. Germline mutations, which prevent normal KTS splicing, can underlie the Denys-Drash syndrome, and disruptions of splicing of exon 5 may occur in Wilms tumours. We analysed by reverse transcriptase polymerase chain reaction (RT-PCR) amplification the relative ratios of the four splice variants of WTI mRNA in normal and tumour tissues and found tissue-specific, developmental stage-specific, and species-specific differences in the splicing of exon 5 but not of KTS. We found no evidence for disrupted splicing in acute leukaemias or gonadal tumours. The significance of these findings is discussed, and the possibility is raised that WTI may orchestrate the appropriate response to growth and differentiation factor signalling, mediated by alterations in the relative levels of exon 5 containing WTI isoforms.

Alternative Splicing↗

PubMed1998

Selective deletion of exon 1 beta of the p19ARF gene in metastatic melanoma cell lines.

The INK4A locus on 9p21 is deleted or rearranged in a large number of human cancers. The locus encodes two unrelated and independently acting negative cell-cycle regulators, p16 and p19ARF, arising in alternate reading frames from a partly shared sequence. We analyzed five human melanoma cell lines for deletions at the INK4 loci and flanking microsatellite markers on 9p21. All the cell lines displayed deletions of varying sizes. The metastatic cell line IGR-1 showed a large deletion between the markers D9S736 and D9S171. In the cell lines WM-115 and WM-266-4, the deletion included exon 1alpha of p16, exon 1beta of p19ARF, and exon 2 of the INK4B (p15) gene. Two cell lines, SK-MEL-5 and A2058, had deletions confined to exon 1beta and the microsatellite marker D9S942. RT-PCR experiments showed the presence of the p16 and p15 transcripts and absence of p19ARF expression in both SK-MEL-5 and A2058 cell lines. The selective loss of the exon 1beta of p19ARF and retention of the p16 and p15 genes and their expressions in these two cell lines support the putative tumor suppressor role for the alternate reading frame p19ARF gene.

Cell Cycle Proteins↗

PubMed2000

Analysis of the NF1 gene by temperature gradient gel electrophoresis reveals a high incidence of mutations in exon 4b.

A total of 196 unrelated patients with neurofibromatosis type 1 (NF1) was screened for mutations in exons 4a-c of the NF1 gene by temperature gradient gel electrophoresis (TGGE) of polymerase chain reaction (PCR)-amplified genomic DNA fragments using intron-based primers. DNA samples with abnormal TGGE band patterns were subjected to sequence analysis. Sequence alterations were identified in ten patients (5.1%): 496delGT (1), 499delTGTT (4), T528A = D176E (2), T539A = L180X (1), 540insA (1), C574T = R192X (1). Thus, a total of six different mutations was identified in exon 4b but none in exons 4a and 4c. Only the missense mutation D176E, which we assume to be a nonpathogenic polymorphism, and the 4-base pair (bp) deletion 499delTGTT have been described before. The reason for the high incidence of mutations in exon 4b is obviously a tetranucleotide tandem repeat comprising nucleotides 495-502 (TGTTTGTT) that may give rise to slipped mispairing and subsequent deletion of one repeat unit during replication. Additionally, the recurrent 4 bp deletion was found as a second hit in a malignant schwannoma of a further NF1 patient, suggesting that microlesions may be as frequent among somatic as among germline mutations. This is the first report of a systematic study of NF1 exons 4a-c in a large group of NF1 patients.

Base Sequence↗

PubMed2001

Rapid detection by fluorescent multiplex PCR of exon deletions and duplications in the C1 inhibitor gene of hereditary angioedema patients.

Hereditary angioedema (HAE) is due to a variety of defects in the C1 inhibitor gene (C1NH gene), including approximately 20% of partial deletions/duplications whose boundaries are usually within Alu repeats. To ensure complete molecular characterization of C1 inhibitor deficiencies a fluorescent multiplex assay was constructed to amplify simultaneously five exons of C1NH and an exon of the BRCA1 gene. PCR protocols were optimized for these amplicons (size range between 300 and 700 bp). Forward and reverse chimeric primers that carry strand-specific 5' tags of 16 nucleotides were used to ensure similar levels of PCR products for each amplicon in the multiplex. Data were analyzed by superposing fluorescent profiles of test and control DNA and by visually comparing the normalized peak levels of corresponding amplicons, rather than by calculating the ratios of peak areas. Tests on a collection of known defects, including five different Alu-mediated deletions and a partial duplication have validated this approach. In a study of 19 sporadic cases of HAE, of which four had failed to reveal mutations upon screening all exons by fluorescent chemical cleavage, three de novo deletions were diagnosed by using this multiplex PCR approach: a deletion of exon 4, a deletion of exons 5 and 6, and an apparently complete gene deletion. Besides being suitable for the initial DNA screening of the C1NH gene in HAE patients prior to screening for point mutations, this method can be easily adapted to complex genes for the screening of rearrangements.

Angioedema↗

PubMed2001

Exon skipping in the ATM gene in normal individuals: the effect of blood sample storage on RT-PCR analysis.

Mutations in ATM, the gene defective in the human genetic disorder ataxia-telangiectasia (A-T), have been described in A-T patients and in a variety of tumor samples. Most of these arise due to exon skipping. We developed an RT-PCR based protein truncation test (PTT) to screen for ATM mutations in breast cancer patients showing adverse response to radiotherapy. An additional PTT product was evident in the ATM gene in peripheral blood mononuclear cells (PBMCs) from blood samples that were collected 2 days or more prior to RNA extraction. Lymphoblastoid cell lines established from the same blood samples showed no evidence of the additional band. Cloning and sequencing of the additional RT-PCR product revealed an exact deletion of exon 20 (2639 del 200), pointing to exon skipping. RT-PCR analysis of RNA extracted from freshly prepared PBMCs from 3 normal individuals showed no evidence of the additional RT-PCR product but when the blood was stored for 2-3 days prior to RNA extraction the lower molecular weight band was evident in every sample. DNA sequencing confirmed this to be due to loss of exon 20. These data suggest that mRNA-based mutation analysis on ATM should be carried out on unstored blood samples to avoid artificial loss of exons that give rise to apparent mutations.

Alternative Splicing↗

PubMed1995

Isolation of genes from the Batten candidate region using exon amplification. Batten Disease Consortium.

In order to identify genes originating from the Batten disease candidate region, we have used the technique of exon amplification to identify transcribed sequences. This procedure produces trapped exon clones, which can represent single exons or multiple exons spliced together and is an efficient method for obtaining probes for physical mapping and for screening cDNA libraries. The source of DNA for these experiments was a collection of chromosome 16 cosmid contigs isolated by the direct subcloning of region-specific yeast artificial chromosomes (YACs) and hybridization of inter-alu PCR products from these YACs to the flow-sorted Los Alamos chromosome 16 cosmid library. We are now using the resulting exon probes to screen retina and brain cDNA libraries for candidate JNCL genes.

Animals↗

PubMed2004

A stop codon mutation in COL11A2 induces exon skipping and leads to non-ocular Stickler syndrome.

Mutations in COL11A2 cause a spectrum of phenotypes affecting chondrogenic tissues. We analyzed this gene by conformation sensitive gel electrophoresis (CSGE) and sequencing in a family with non-ocular Stickler syndrome, and found a heterozygous C --> T mutation in exon 57 + 13 in affected members, resulting in Arg893Stop codon. Since heterozygous nonsense mutations in COL11A2 do not usually lead to any obvious phenotype, all exons and exon boundaries of COL11A2 in the sample of the propositus were sequenced. Because no disease-associated alterations were found, we performed RT-PCR analysis on the RNA. Analysis showed skipping of exon 57 in one allele, resulting in an inframe deletion of 54 bp or 18 amino acids, which would explain the phenotype observed in the family. Thus, the exon skipping resulted from a nonsense-associated altered splicing (NAS). This article contains supplementary material, which may be viewed at the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/0148-7299/suppmat/index.html.

Abnormalities, Multiple↗

PubMed2003

Association of EEG coherence and an exonic GABA(B)R1 gene polymorphism.

The GABA(B) receptor 1 gene is mapped to chromosome 6p21.3 within the HLA class I region close to the HLA-F gene. Susceptibility loci for epilepsy and schizophrenia have been mapped in this region. Based on pharmacological evidence, it has been suggested that GABA(B) receptors may play a crucial role in the synchronization of EEG oscillations, which in turn can be abnormal in neuropsychiatric disorders. In the present study, the hypothesis was tested, whether three exonic variants of the gene encoding the human GABA(B) receptor (GABA(B)R1) modify cortical synchronization measured as scalp-recorded EEG-coherence. Two principal components of EEG coherence (frontal coherence, parietotemporal coherence) were investigated in 104 healthy subjects during three conditions: resting EEG, activated EEG, and event-related EEG. No significant associations were found between the frontal coherence component and any polymorphism or between the parietotemporal coherence component and the exon 1a1 polymorphism. However, parietotemporal coherence showed statistically highly significant associations across all three experimental conditions with exon 7 and trend associations with exon 11. The results provide evidence that the translated polymorphism of exon 7 may be functionally meaningful and impact cortical EEG oscillations. Since variations of EEG coherence have been described for several neuropsychiatric disorders, the present association should be tested in clinical samples using EEG coherence as an intermediate phenotype.

Adult↗

PubMed1995

A point mutation in the human CD45 gene associated with defective splicing of exon A.

CD45 is a receptor-type protein tyrosine phosphatase involved in the regulation of lymphocyte activation. Different CD45 isoforms are generated by alternative splicing of three variable exons (A, B and C). The pattern of CD45 splicing depends upon cell type and state of activation. CD45RA isoforms (containing exon A-encoded sequences) can usually be found on a subset of resting T cells, but not on activated T cells. We have recently described a variant pattern of CD45RA expression which is characterized by continuous expression of CD45RA molecules on activated and memory T cells. Here, we demonstrate that this phenotype is associated with heterozygosity for a point mutation at nucleotide position 77 of exon A, leading to a C-->G transition. This mutation does not change the protein sequence of the CD45RA isoform. We conclude that position 77 is part of a motif necessary for splicing of exon A, which supports the hypothesis that sequences within exons have significant effects on alternative splicing. The mutation of this motif might prevent binding of a transacting splice factor. In the heterozygous state, this mutation is not associated with impaired T cell reactivity. Functional consequences of the homozygous state remain to be elucidated.

Base Sequence↗

PubMed2003

Deletion of Brca2 exon 27 causes hypersensitivity to DNA crosslinks, chromosomal instability, and reduced life span in mice.

The Brca2 tumor-suppressor gene contributes to genomic stability, at least in part by a role in homologous recombinational repair. BRCA2 protein is presumed to function in homologous recombination through interactions with RAD51. Both exons 11 and 27 of Brca2 code for domains that interact with RAD51; exon 11 encodes eight BRC motifs, whereas exon 27 encodes a single, distinct interaction domain. Deletion of all RAD51-interacting domains causes embryonic lethality in mice. A less severe phenotype is seen with BRAC2 truncations that preserve some, but not all, of the BRC motifs. These mice can survive beyond weaning, but are runted and infertile, and die very young from cancer. Cells from such mice show hypersensitivity to some genotoxic agents and chromosomal instability. Here, we have analyzed mice and cells with a deletion of only the RAD51-interacting region encoded by exon 27. Mice homozygous for this mutation (called brca2(lex1)) have a shorter life span than that of control littermates, possibly because of early onsets of cancer and sepsis. No other phenotype was observed in these animals; therefore, the brca2(lex1) mutation is less severe than truncations that delete some BRC motifs. However, at the cellular level, the brca2(lex1) mutation causes reduced viability, hypersensitivity to the DNA interstrand crosslinking agent mitomycin C, and gross chromosomal instability, much like more severe truncations. Thus, the extreme carboxy-terminal region encoded by exon 27 is important for BRCA2 function, probably because it is required for a fully functional interaction between BRCA2 and RAD51.

Animals↗

PubMed2005

A recurrent duodenal gastrointestinal stromal tumor with a frameshift mutation resulting in a stop codon in KIT exon 13.

Gastrointestinal stromal tumors (GISTs) are a specific and rare subset of human gastrointestinal tract tumors. Most GISTs show gain-of-function mutations of KIT, mainly in exon 11, that always maintain the reading frame. We report on data from a 43-year-old Japanese man with recurrent duodenal GIST and a frameshift mutation in KIT exon 13 together with an in-frame deletion in KIT exon 11 detected by genomic DNA sequencing. Deletion of 48 base pairs of KIT exon 11, which preserved the reading frame, was identified in both primary and recurrent tumors, whereas deletion of one nucleotide of codon 642 of KIT exon 13, which changed the reading frame and induced a novel stop codon at amino acid 644, was found only in the recurrent tumor. The predicted protein resulting from the latter would lack part of the kinase domain. To the best of our knowledge, this is the first documentation of a GIST with a frameshift mutation of KIT.

Adult↗