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Polymorphisms in a pseudogene highly homologous to PMS2
R B Chadwick1, J E Meek, T W Prior
1Division of Human Cancer Genetics, The Ohio State University, Columbus, Ohio, USA.
Abstract:
PMS2 is one of a complex of genes encoding DNA repair proteins that includes MSH2, MLH1, MSH6 and MSH3. Mutation of any of these DNA mismatch repair genes leads to impairment of DNA repair and can lead to tumorigenesis. Germline mutation of PMS2 has been reported as a rare cause of hereditary nonpolyposis colorectal cancer (HNPCC) and Turcot's syndrome. The PMS2 gene is located on chromosome 7p22 and consists of 15 exons. Within exon 11 of PMS2 is a coding repeat of eight adenosines. This study reports on the finding of a nonexpressed pseudogene that is highly homologous to the PMS2 gene in this region. The pseudogene is polymorphic for two alterations in the repeat region: a 3 bp delAAA at a site corresponding to nucleotide 1231 in PMS2; and an AA-->GG change at nucleotide 1238. Due to the high homology in both intronic and exonic sequences, polymorphisms in this pseudogene could be mistaken for mutations in the PMS2 gene and erroneously thought to be a cause of HNPCC and/or Turcot's syndrome.
Insights
A newly discovered pseudogene highly similar to the PMS2 gene may be mistaken for actual PMS2 mutations. This finding is crucial for accurate diagnosis of hereditary nonpolyposis colorectal cancer and Turcot's syndrome.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- The PMS2 gene is part of a DNA repair complex crucial for preventing tumorigenesis.
- Germline mutations in PMS2 are rare causes of hereditary nonpolyposis colorectal cancer (HNPCC) and Turcot's syndrome.
Purpose of the Study:
- To identify and characterize a highly homologous pseudogene of PMS2.
- To investigate potential diagnostic challenges arising from pseudogene polymorphisms.
Main Methods:
- Bioinformatic analysis to identify homologous sequences.
- Sequence analysis of the PMS2 gene and its pseudogene, focusing on exon 11 repeat regions.
Main Results:
- A nonexpressed pseudogene highly homologous to PMS2 was identified.
- This pseudogene exhibits polymorphisms in the repeat region, including a 3 bp deletion and an AA to GG substitution.
- High sequence homology extends to both intronic and exonic regions.
Conclusions:
- Polymorphisms in the PMS2 pseudogene can be erroneously interpreted as pathogenic mutations.
- This misinterpretation could lead to incorrect diagnoses of HNPCC and/or Turcot's syndrome.
- Awareness of this pseudogene is essential for accurate genetic testing and counseling.