Insertion of an Alu-like element in MLH1 intron 7 as a novel cause of Lynch syndrome.

Abstract

BACKGROUND:

Lynch Syndrome (LS) is caused by germline mutations in the DNA mismatch repair (MMR) genes with mutations in MLH1 accounting for ~40% of LS-related alterations.

METHODS:

MSK-IMPACT analysis was performed on peripheral blood from a patient with early- onset colorectal cancer. Subsequently PCR and sequencing was performed to characterize the insertion. Immunohistochemistry for MMR genes and MLH1 promoter methylation were analyzed on patient's tumor.

RESULTS:

MSK-IMPACT germline testing revealed an insertion into c.588+8_588+9 of MLH1 intron 7. The insertion was further characterized as an AluSx-like element with ~115 bp in length. Functional studies demonstrated that the AluSx-like element led to complete disruption of mRNA splicing and probably resulted in transcriptional termination at the poly (A) region of the AluSx-like insertion.

CONCLUSIONS:

The insertion of a truncated AluSx like element into MLH1 intron 7 results in aberrant splicing and transcription, thereby causing Lynch syndrome. This study confirms that retrotransposon insertions may be an important mechanism for cancer predisposition.

• Authors: Yirong Li, Erin Salo-Mullen, Anna Varghese, Magan Trottier, Zsofia K Stadler, Liying Zhang
• Journal: Molecular genetics & genomic medicine (Mol Genet Genomic Med) Vol. 8 Issue 12 Pg. e1523 (12 2020) ISSN: 2324-9269 [Electronic] United States
• PMID: 33058565 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.

Chemical References

• MLH1 protein, human
• MutL Protein Homolog 1

Topics

• Adult
• Alu Elements
• Colorectal Neoplasms, Hereditary Nonpolyposis (genetics, pathology)
• Humans
• Introns
• Male
• MutL Protein Homolog 1 (genetics)
• Mutagenesis, Insertional
• RNA Splicing