Missense and nonsense mutations in codon 659 ofMLH1 cause aberrant splicing of messenger RNA in HNPCC kindreds

Nyström‐Lahti, Minna; Holmberg, Mari T.; Fidalgo, Paulo; Salovaara, Reijo; A, de la Chapelle; Jiricny, Josef; Peltomäki, Païvi

doi:10.1002/(sici)1098-2264(199912)26:4<372::aid-gcc12>3.0.co;2-v

Cited by 35 publications

(23 citation statements)

References 14 publications

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“…This mutation has previously been reported to result in aberrant splicing with deletion of exon 17, thereby leading to a non-functional protein. 26 Segregation analysis also supported a pathogenic role for this mutation as affected members (II:2 and III:1; fig 1) were shown to carry this same mutation while II:5 did not. MSI was positive in 2/5 markers and nuclear expression of the hMLH1 gene was absent in tumour tissue from one affected patient.…”

Section: Resultsmentioning

confidence: 76%

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Pathogenicity of missense and splice site mutations in hMSH2 and hMLH1 mismatch repair genes: implications for genetic testing

Cravo

Afonso

Lage

et al. 2002

Gut

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Background: In hereditary non-polyposis colorectal cancer, over 90% of the identified mutations are in two genes, hMSH2 and hMLH1. A large proportion of the mutations detected in these genes are of the missense type which may be either deleterious mutations or harmless polymorphisms. Aim: To investigate whether nine missense and one splice site mutation of hMLH1 and hMSH2, in 10 kindreds with a familial history of colorectal cancer or young age of onset, could be interpreted as pathogenic. Methods: Clinical and genetic characteristics were collected: (i) evolutionary conservation of the codon involved; (ii) type of amino acid change; (iii) occurrence of mutation in healthy controls; (iv) cosegregation of mutation with disease phenotype; (v) functional consequences of gene variant; and (vi) microssatellite instability and immunoexpression of hMSH2 and hMLH1 analysis. Results: Seven different missense and one splice site mutation were identified. Only 1/8 was found in the control group, 2/7 occurred in conserved residues, and 5/7 resulted in non-conservative changes. Functional studies were available for only 2/8 mutations. Segregation of the missense variant with disease phenotype was observed in three kindreds. Conclusion: In the majority of families included, there was no definitive evidence that the missense or splice site alterations were causally associated with an increased risk of developing colorectal cancer. Until further evidence is available, these mutational events should be regarded and interpreted carefully and genetic diagnosis should not be offered to these kindreds.

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Section: Resultsmentioning

confidence: 76%

“…†Despite this mutation resulting in an amino acid change, it also results in an aberrant splicing leading to exon 17 deletion, as was previously described. 26 ‡Three or less affected members were available per family. 12 §All other affected members of the family were deceased, or unable to contact other family members.…”

Section: Resultsmentioning

confidence: 99%

Pathogenicity of missense and splice site mutations in hMSH2 and hMLH1 mismatch repair genes: implications for genetic testing

Cravo

Afonso

Lage

et al. 2002

Gut

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“…The RNA-based methods overcome these points and are also useful for detecting exon skipping caused by splice-site or branch-point mutations. 40,41 However, because multiple mRNA isoforms have been reported for both genes, 42,43 the variants of exon deletion at the RNA level must be confirmed by the detection of causative mutations in genomic DNA. With this reservation in mind, the RNA-based methods are useful for screening gene mutations because they do not require much time.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of screening strategy for detecting hereditary nonpolyposis colorectal carcinoma

Furukawa

Konishi

Shitoh

et al. 2002

Cancer

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The synthesis of well‐defined 3‐ and 4‐miktoarm star copolymers of the A2B and A3B types is described, where A is 1,4‐polybutadiene and B is poly(1,3‐cyclohexadiene). The synthetic approach involves the reaction of poly(1,3‐cyclohexadienyl)lithium with an excess of methyltrichlorosilane or tetrachlorosilane followed, after the removal of excess silane, by a small excess of polybutadienyllithium. Characterization was carried out by size exclusion chromatography, low‐angle laser light scattering, laser differential refractometry, and NMR spectroscopy. The complete heterogeneous catalytic hydrogenation of the A2B and A3B miktoarm stars, with a calcium carbonate‐supported palladium catalyst, leads to the formation of A2B and A3B miktoarm stars with one amorphous polycyclohexylene arm with an extremely high glass‐transition temperature and two or three crystalline polyethylene arms. Differential scanning calorimetry was used to determine the glass‐transition temperature of the amorphous blocks of the starting and hydrogenated stars and the melting temperature of polyethylene. Solid‐state 13C NMR spectroscopy was performed to ensure the complete saturation of the polycyclohexadiene and polybutadiene arms. © 2002 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 40: 2575–2582, 2002

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“…Also, in various hereditary nonpolyposis colorectal cancer kindreds, different mutations in codon 659 result in skipping of exon 17 of the mismatch repair protein MLH1. This causes an internal deletion of 31 amino acids that abrogates binding to the other mismatch repair protein PMS2 (18).…”

Section: Splice Site Mutations Can Cause Aberrant Splicing and Cancermentioning

confidence: 99%

Aberrant and Alternative Splicing in Cancer

2004

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Pre-mRNA splicing is a sophisticated and ubiquitous nuclear process, which is a natural source of cancer-causing errors in gene expression. Intronic splice site mutations of tumor suppressor genes often cause exon-skipping events that truncate proteins just like classical nonsense mutations. Also, many studies over the last 20 years have reported cancerspecific alternative splicing in the absence of genomic mutations. Affected proteins include transcription factors, cell signal transducers, and components of the extracellular matrix. Antibodies against alternatively spliced products on cancer cells are currently in clinical trials, and competitive reverse transcription-PCR across regions of alternative splicing is being used as a simple diagnostic test. As well as being associated with cancer, the nature of the alternative gene products is usually consistent with an active role in cancer; therefore, the alternative splicing process itself is a potential target for gene therapy. Splice Site Mutations Can Cause Aberrant Splicing and CancerDefects in mRNA splicing are an important cause of disease (1-3). The most common form of splicing defects are genomic splice site point mutations, and a recent survey found 29 different p53 splice site mutations in Ͼ12 different types of cancer (4). Ninety-nine percent of all exons are flanked by the intronic dinucleotides GT and AG at the 5Ј and 3Ј splice sites respectively, and mutation of these sites usually causes exclusion of the adjacent exon (Fig. 1A), although sometimes splice site mutations have even more drastic consequences, e.g., double exon skipping in MLH1 in hereditary nonpolyposis colorectal cancer (5). More than half of all exon deletions lead to truncation of the encoded protein and as such, mutations in tumor suppressor genes at the invariant intronic dinucleotide can act much as classical nonsense mutations. For example a GT to AT 5Ј splice site mutation in hSNF5 causes deletion of exon 7, a frame shift, and a truncated reading frame, and this causes infant brain tumors when a "second hit" is provided at the wild-type allele by a deletion (6). Similarly a 3Ј splice site AG to AT mutation caused constitutive loss of exon 4 of the APC gene in colorectal to liver metastases, where the wild-type allele was deleted (ref. 7; Fig. 1A).Mutations in the less conserved splice site consensus away from the invariant dinucleotides tend to lead to partial aberrant splicing, often with a relatively mild phenotype. For example, the most common pathogenic mutation of the ATM gene is linked to breast cancer but is incompletely penetrant and is thought to have originated in Palaeolithic times. This is a mutation at the sixth position of an intron that causes a proportion of transcripts to skip an exon and to be frame shifted leading to a truncated protein (8). The polypyrimidine tract signal associated with the 3Ј splice site is another hot spot for mutation (Fig. 1A). An intronic mutation 11 nucleotides upstream of a 3Ј splice site in MLH1 knocks out an exon, and this ...

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Missense and nonsense mutations in codon 659 ofMLH1 cause aberrant splicing of messenger RNA in HNPCC kindreds

Cited by 35 publications

References 14 publications

Pathogenicity of missense and splice site mutations in hMSH2 and hMLH1 mismatch repair genes: implications for genetic testing

Pathogenicity of missense and splice site mutations in hMSH2 and hMLH1 mismatch repair genes: implications for genetic testing

Evaluation of screening strategy for detecting hereditary nonpolyposis colorectal carcinoma

Aberrant and Alternative Splicing in Cancer

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