Eight novel inactivating germ line mutations at the APC gene identified by denaturing gradient gel electrophoresis

Fodde, Riccardo; Luijt, Rob van der; Wijnen, Juul T.; Tops, Carli M.J.; Klift, Heleen van der; Leeuwen-Cornelisse, Inge van; Griffioen, G.; Vasen, Hans F. A.; Khan, P. Meera

doi:10.1016/0888-7543(92)90032-n

Cited by 94 publications

(44 citation statements)

References 26 publications

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“…In screening for mutations of the APC gene, many techniques, such as SSCP analysis (Groden et al 1991) , denaturing gradient gel electrophoresis (DGGE) (Fodde et al 1992), and ribonuclease protection assay (RPA) , have been employed. SSCP and DGGE have been preferentially used for their simplicity.…”

Section: Resultsmentioning

confidence: 99%

Germline mutations of the APC gene in Korean familial adenomatous polyposis patients

et al. 1999

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We extensively analyzed genomic DNA and messenger RNA (mRNA) from 62 unrelated Korean patients with familial adenomatous polyposis (FAP) for identification of germline adenomatous polyposis coli (APC) gene mutations. We adopted both single-strand conformation polymorphism (SSCP) analysis and a method of analysis involving the reverse transcription-polymerase chain reaction (RT-PCR) followed by a protein truncation test (PTT). DNA sequencing confirmed all alterations represented by aberrant bands. Germline mutations were identified in 38 patients (61%). Nineteen of the detected mutations were presumed to be novel, thus emphasizing the heterogeneity of the mutational spectrum in Korean FAP patients. In the initial 48 patients, SSCP analysis was followed by PTT for those patients for whom no detectable mutations were found by SSCP. Using this combined approach, we identified germline APC gene mutations in 29 of the 48 FAP patients (60%), including 6 patients in whom SSCP analysis failed to distinguish the mutant allele. In the 14 later patients, we identified truncating mutations in 9 patients (64%) using PTT only. Our results confirm that the mutation detection rate with PTT was superior to that with SSCP, and suggest that PTT would be a more practical screening method to detect germline mutations of the APC gene in FAP patients.

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Section: Resultsmentioning

confidence: 99%

Germline mutations of the APC gene in Korean familial adenomatous polyposis patients

et al. 1999

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“…This event serves to decrease the C1 complexity of a sequence. Thus, for example, a short micro-deletion in the APC gene [Fodde et al, 1992] [AAAGAAATAGatag-TCTTCCTTTA] gives rise to a slight decrease in complexity C1 from 13 to 12. As follows from decompositions (1) and (2), two copies of a direct repeat thought to have been responsible for mediating the micro-deletion are underlined.…”

Section: Mechanisms Of Mutagenesis and Sequence Complexitymentioning

confidence: 99%

Meta-analysis of indels causing human genetic disease: mechanisms of mutagenesis and the role of local DNA sequence complexity

et al. 2002

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Communicated by Stylianos E. AntonarakisA relatively rare type of mutation causing human genetic disease is the indel, a complex lesion that appears to represent a combination of micro-deletion and micro-insertion. In the absence of metaanalytical studies of indels, the mutational mechanisms underlying indel formation remain unclear. Data from the Human Gene Mutation Database (HGMD) were therefore used to compare and contrast 211 different indels underlying genetic disease in an attempt to deduce the processes responsible for their genesis. Each indel was treated as if it were the result of a two-step insertion/deletion process and was assessed in the context of 10 base-pairs DNA sequence flanking the lesion on either side. Several indel hotspots were noted and a GTAAGT motif was found to be significantly over-represented in the vicinity of the indels studied. Previously postulated mechanisms underlying micro-deletions and micro-insertions were initially explored in terms of local DNA sequence regularity as measured by its complexity. The change in complexity consequent to a mutation was found to be indicative of the type of repeat sequence involved in mediating the event, thereby providing clues as to the underlying mutational mechanism. Complexity analysis was then employed to examine the possible intermediates through which each indel could have occurred and to propose likely mechanisms and pathways for indel generation on an individual basis. Manual analysis served to confirm that the majority of indels (490%) are explicable in terms of a two-step process involving established mutational mechanisms. Indels equivalent to double base-pair substitutions (22% of the total) were found to be mechanistically indistinguishable from the remainder and may therefore be regarded as a special type of indel. The observed correspondence between changes in local DNA sequence complexity and the involvement of specific mutational mechanisms in the insertion/deletion process, and the ability of generated models to account for both the number and identity of the bases deleted and/or inserted, makes this approach invaluable not only for the analysis of indel formation, but also for the study of other types of complex lesion. Hum Mutat 21:28-44,

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“…the NTHL1 gene with a recessive inheritance of the phenotype, predisposing to BER associated adenomatous polyposis and CRC (Weren et al, 2015). However, in the attenuated and mixed polyposis syndromes only a fraction of the disease‐causing mutations can still be identified (Fodde et al, 1992; Miyoshi et al, 1992; Lynch et al, 1995). The low mutation‐detection rate implicates the probable presence of additional unknown disease‐causing genes and possibly also recognition of new mutation mechanisms.…”

Section: Introductionmentioning

confidence: 99%

GREM1 and POLE variants in hereditary colorectal cancer syndromes

Rohlin

Eiengård

Lundstam

et al. 2015

Genes Chromosomes & Cancer

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Hereditary factors are thought to play a role in at least one third of patients with colorectal cancer (CRC) but only a limited proportion of these have mutations in known high‐penetrant genes. In a relatively large part of patients with a few or multiple colorectal polyps the underlying genetic cause of the disease is still unknown. Using exome sequencing in combination with linkage analyses together with detection of copy‐number variations (CNV), we have identified a duplication in the regulatory region of the GREM1 gene in a family with an attenuated/atypical polyposis syndrome. In addition, 107 patients with colorectal cancer and/or polyposis were analyzed for mutations in the candidate genes identified. We also performed screening of the exonuclease domain of the POLE gene in a subset of these patients. The duplication of 16 kb in the regulatory region of GREM1 was found to be disease‐causing in the family. Functional analyses revealed a higher expression of the GREM1 gene in colorectal tissue in duplication carriers. Screening of the exonuclease domain of POLE in additional CRC patients identified a probable causative novel variant c.1274A>G, p.Lys425Arg. In conclusion a high penetrant duplication in the regulatory region of GREM1, predisposing to CRC, was identified in a family with attenuated/atypical polyposis. A POLE variant was identified in a patient with early onset CRC and a microsatellite stable (MSS) tumor. Mutations leading to increased expression of genes can constitute disease‐causing mutations in hereditary CRC syndromes. © 2015 The Authors. Genes, Chromosomes & Cancer Published by Wiley Periodicals, Inc.

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Eight novel inactivating germ line mutations at the APC gene identified by denaturing gradient gel electrophoresis

Cited by 94 publications

References 26 publications

Germline mutations of the APC gene in Korean familial adenomatous polyposis patients

Germline mutations of the APC gene in Korean familial adenomatous polyposis patients

Meta-analysis of indels causing human genetic disease: mechanisms of mutagenesis and the role of local DNA sequence complexity

GREM1 and POLE variants in hereditary colorectal cancer syndromes

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