Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial hypercholesterolemia (FH) results from defective low-density lipoprotein receptor (LDLR) activity, mainly due to LDLR gene defects. Of the many different LDLR mutations found in patients with FH, about 6% of single base substitutions are located near or within introns, and are predicted to result in exon skipping, retention of an intron, or activation of cryptic sites during mRNA splicing. This paper reports on the Portuguese FH Study, which found 10 such mutations, 6 of them novel. For the mutations that have not been described before or those whose effect on function have not been analysed, their effect on splicing was investigated, using reverse transcriptase PCR analysis of LDLR mRNA from freshly isolated blood mononuclear cells. Two of these variants (c.313+6 T-->C, c.2389G-->T (p.V776L)) caused exon skipping, and one caused retention of an intron (c.1359-5C-->G), whereas two others (c.2140+5 G-->A and c.1061-8T-->C) had no apparent effect. Any effect of c.1185G-->C (p.V374V) on splicing could not be determined because it was on an allele with a promoter mutation (-42C-->G) that was probably not transcribed. Variants in four patients lost to follow-up could not be tested experimentally, but they almost certainly affect splicing because they disrupt the invariant AG or GT in acceptor (c.818-2A-->G) or donor (c.1060+1G-->A, c.1845+1delG and c.2547+1G-->A) spice sites. These findings emphasise that care must be taken before reporting the presence or absence of a splice-site mutation in the LDLR gene for diagnostic purposes. The study also shows that relatively simple, quick and inexpensive RNA assays can evaluate putative splicing mutations that are not always predictable by available software, thereby reducing genetic misdiagnosis of patients with FH.
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PMID:Genetic diagnosis of familial hypercholesterolaemia: the importance of functional analysis of potential splice-site mutations. 1941 63

Unusual MLL gene rearrangements were found in bone marrow cells of four patients with acute myeloid leukemia. A combination of conventional and molecular cytogenetic methods were used to describe translocations t(9;12;11)(p22;p13;q23), t(11;19)(q23;p13.3), and t(10;11)(p12;23) and inverted insertion ins(10;11)(p12;q23.3q23.1). Partial nontandem duplication of the MLL gene was identified by reverse transcriptase-polymerase chain reaction in all cases. The duplication, which included MLL exons 2 through 8-9, was interrupted by a cryptic insertion of one or two exons from the respective MLL partner gene: MLLT10, MLLT3, or MLLT1.
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PMID:A partial nontandem duplication of the MLL gene in four patients with acute myeloid leukemia. 1996 15

A 57-yr-old woman was diagnosed with acute myeloid leukemia (AML) with maturation, based on morphological and cytochemical/immunophenotypic findings on bone marrow studies. Conventional cytogenetic analysis using bone marrow cells revealed terminal deletion of the short arm of an X chromosome as 46,X,del(X)(p21)[8]/46,XX[12]. On the other hand, fluorescence in situ hybridization (FISH) for the RUNX1/RUNX1T1 (formerly AML1/ETO) rearrangement revealed 86% interphase nuclei with one fusion signal, which was found to be on the long arm of chromosome 8 on metaphase FISH, indicating the RUNX1/RUNX1T1 rearrangement by cryptic insertion of the RUNX1 gene. Molecular genetic study by reverse transcriptase polymerase chain reaction (RT-PCR) confirmed the presence of the chimeric transcript. The final karyotype was 46,X,del(X)(p21).ish ins(8;21)(q22;q22q22)(RUNX1T1+,RUNX1+;RU NX1+,RUNX1T1-)[8]/46,XX[12]. In addition to the cryptic RUNX1/RUNX1T1 rearrangement, this is the first report of partial deletion of an X chromosome as an additional cytogenetic aberration in AML with RUNX1/RUNX1T1.
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PMID:Acute myeloid leukemia with del(X)(p21) and cryptic RUNX1/RUNX1T1 from ins(8;21)(q22;q22q22) revealed by atypical FISH signals. 2012 35

Our patient was a 52-year-old man who was diagnosed with signet ring cell gastric adenocarcinoma. An extensive family history of gastric cancer raised suspicion for hereditary diffuse gastric cancer. Sequencing of the patient's CDH1 gene revealed a novel point mutation in a strictly conserved splice site within intron 6, c.833-2 A > G. This mutation was predicted to result in loss of function due to defective RNA splicing. To characterize the pathogenic mechanism of this mutation, we amplified the patient's CDH1 gene products by reverse transcriptase polymerase chain reaction. Primers flanking the region of the mutation detected 3 distinct transcripts. In addition to the wild-type product, a larger product consistent with activation of a cryptic splice site within intron 6 and a smaller product shown to result from exon 7 skipping were detected. In summary, we have identified a novel CDH1 mutation in a large hereditary diffuse gastric cancer kindred and identified its pathogenic mechanism.
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PMID:Hereditary diffuse gastric cancer due to a previously undescribed CDH1 splice site mutation. 2062 23

Cryptic deletions are occasionally reported in hematologic malignancies. The SET-NUP214 fusion gene has been rarely reported in acute myeloid leukemia, acute undifferentiated leukemia, and recurrently in T-cell acute lymphoblastic leukemia. The fusion product is generated by a submicroscopic deletion in the vicinity of 9q34. Herein we present a novel case of acute undifferentiated leukemia with SET-NUP214 rearrangement due to the cryptic deletion of the 9q34 region producing two different types of fusion transcripts by alternative splicing and molecular characterization of the fusion transcripts by fluorescence in situ hybridization, reverse transcriptase-polymerase chain reaction, and array comparative genomic hybridization analyses.
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PMID:Molecular characterization of alternative SET-NUP214 fusion transcripts in a case of acute undifferentiated leukemia. 2068 90

Reverse transcription-PCR (RT-PCR) describes a technique whereby RNA is first reverse transcribed into complementary DNA (cDNA) using the enzyme reverse transcriptase, and the resulting cDNA amplified in either a single-step or a two-step nested PCR reaction. It is particularly useful for detecting molecular markers associated with leukaemia, as it enables a single assay to be used for many patients, each with unique genomic translocation breakpoints, but who have common fusion points in mRNA. This molecular method can not only detect aberrations that are cytogenetically cryptic, such as t(12;21)(p13;q22) in paediatric acute lymphoblastic leukaemia (ALL), but is also very sensitive, and as such can be used to monitor minimal residual disease (MRD). Detecting and measuring MRD is important because it can be a guide to determining prognosis and relapse risk, predict recurrence of leukaemia, and enable individualization of treatment.
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PMID:Detection of minimal residual disease in leukaemia by RT-PCR. 2093 45

In this study, we correlated the results of concurrent molecular and cytogenetic detection of entity-defining translocations in adults with acute leukemia to determine the frequency of cryptic translocations missed by conventional cytogenetics (CC) and of recurrent, prognostically relevant translocations not detectable by multiplex reverse transcriptase-polymerase chain reaction (MRP). During a 5.5-year period, 442 diagnostic acute leukemia specimens were submitted for MRP-based detection of 7 common recurrent translocations: t(8;21), t(15;17), inv(16), t(9;22), t(12;21), t(4;11), and t(1;19), with a detection rate of 15.2% (67/442). CC was performed in 330 (74.7%) of 442 cases. In 7 of these 330 cases, CC missed the translocation detected by MRP. In 50 additional cases, CC revealed 1 of the MRP-detectable translocations (all were also MRP positive), yielding a false-negative rate of 12% (7/57) for the CC assay. The remaining 140 of 190 cases with clonal cytogenetic changes harbored abnormalities that were not targeted by the MRP assay, including 8 that define specific acute myeloid leukemia entities. This study revealed the frequent occurrence of false-negative, entity-defining CC analysis and highlighted the complementary nature of MRP and CC approaches in detecting genetic abnormalities in acute leukemia.
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PMID:A comparative analysis of molecular genetic and conventional cytogenetic detection of diagnostically important translocations in more than 400 cases of acute leukemia, highlighting the frequency of false-negative conventional cytogenetics. 2157 65

Initiation of reverse transcription in hepadnaviruses is accomplished by a unique protein-priming mechanism whereby a specific Y residue in the terminal protein (TP) domain of the viral reverse transcriptase (RT) acts as a primer to initiate DNA synthesis, which is carried out by the RT domain of the same protein. When separate TP and RT domains from the duck hepatitis B virus (DHBV) RT protein were tested in a trans-complementation assay in vitro, the RT domain could also serve, unexpectedly, as a protein primer for DNA synthesis, as could a TP mutant lacking the authentic primer Y (Y96) residue. Priming at these other, so-called cryptic, priming sites in both the RT and TP domains shared the same requirements as those at Y96. A mini RT protein with both the TP and RT domains linked in cis, as well as the full-length RT protein, could also initiate DNA synthesis using cryptic priming sites. The cryptic priming site(s) in TP was found to be S/T, while those in the RT domain were Y and S/T. As with the authentic TP Y96 priming site, the cryptic priming sites in the TP and RT domains could support DNA polymerization subsequent to the initial covalent linkage of the first nucleotide to the priming amino acid residue. These results provide new insights into the complex mechanisms of protein priming in hepadnaviruses, including the selection of the primer residue and the interactions between the TP and RT domains that is essential for protein priming.
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PMID:Cryptic protein priming sites in two different domains of duck hepatitis B virus reverse transcriptase for initiating DNA synthesis in vitro. 2159 64

Mutations in BRCA1 and BRCA2 predispose carriers to early onset breast and ovarian cancer. A common problem in clinical genetic testing is interpretation of variants with unknown clinical significance. The Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium was initiated to evaluate and implement strategies to characterize the clinical significance of BRCA1 and BRCA2 variants. As an initial project of the ENIGMA Splicing Working Group, we report splicing and multifactorial likelihood analysis of 25 BRCA1 and BRCA2 variants from seven different laboratories. Splicing analysis was performed by reverse transcriptase PCR or mini gene assay, and sequencing to identify aberrant transcripts. The findings were compared to bioinformatic predictions using four programs. The posterior probability of pathogenicity was estimated using multifactorial likelihood analysis, including co-occurrence with a deleterious mutation, segregation and/or report of family history. Abnormal splicing patterns expected to lead to a non-functional protein were observed for 7 variants (BRCA1 c.441+2T>A, c.4184_4185+2del, c.4357+1G>A, c.4987-2A>G, c.5074G>C, BRCA2 c.316+5G>A, and c.8754+3G>C). Combined interpretation of splicing and multifactorial analysis classified an initiation codon variant (BRCA2 c.3G>A) as likely pathogenic, uncertain clinical significance for 7 variants, and indicated low clinical significance or unlikely pathogenicity for another 10 variants. Bioinformatic tools predicted disruption of consensus donor or acceptor sites with high sensitivity, but cryptic site usage was predicted with low specificity, supporting the value of RNA-based assays. The findings also provide further evidence that clinical RNA-based assays should be extended from analysis of invariant dinucleotides to routinely include all variants located within the donor and acceptor consensus splicing sites. Importantly, this study demonstrates the added value of collaboration between laboratories, and across disciplines, to collate and interpret information from clinical testing laboratories to consolidate patient management.
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PMID:Characterization of BRCA1 and BRCA2 splicing variants: a collaborative report by ENIGMA consortium members. 2176 58

SET-NUP214 rearrangements have been rarely reported in T-cell acute lymphoblastic leukemia (T-ALL), acute undifferentiated leukemia, and acute myeloid leukemia, and most documented cases have been associated with normal karyotypes in conventional cytogenetic analyses. Here, we describe a novel case of T-ALL associated with a mediastinal mass and a SET-NUP214 rearrangement, which was masked by a complex karyotype at the time of initial diagnosis. Using multiplex reverse transcriptase-polymerase chain reaction analysis, we detected a cryptic SET-NUP214 rearrangement in our patient. As only 11 cases (including the present study) of T-ALL with SET-NUP214 rearrangement have been reported, the clinical features and treatment outcomes have not been fully determined. Further studies are necessary to evaluate the incidence of SET-NUP214 rearrangement in T-ALL patients and the treatment responses as well as prognosis of these patients.
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PMID:T-cell acute lymphoblastic leukemia associated with complex karyotype and SET-NUP214 rearrangement: a case study and review of the literature. 2207 11


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