PubTransformer

A site to transform Pubmed publications into these bibliographic reference formats: ADS, BibTeX, EndNote, ISI used by the Web of Knowledge, RIS, MEDLINE, Microsoft's Word 2007 XML.

Suspected Lynch syndrome associated MSH6 variants: A functional assay to determine their pathogenicity.

Abstract Lynch syndrome (LS) is a hereditary cancer predisposition caused by inactivating mutations in DNA mismatch repair (MMR) genes. Mutations in the MSH6 DNA MMR gene account for approximately 18% of LS cases. Many LS-associated sequence variants are nonsense and frameshift mutations that clearly abrogate MMR activity. However, missense mutations whose functional implications are unclear are also frequently seen in suspected-LS patients. To conclusively diagnose LS and enroll patients in appropriate surveillance programs to reduce morbidity as well as mortality, the functional consequences of these variants of uncertain clinical significance (VUS) must be defined. We present an oligonucleotide-directed mutagenesis screen for the identification of pathogenic MSH6 VUS. In the screen, the MSH6 variant of interest is introduced into mouse embryonic stem cells by site-directed mutagenesis. Subsequent selection for MMR-deficient cells using the DNA damaging agent 6-thioguanine (6TG) allows the identification of MMR abrogating VUS because solely MMR-deficient cells survive 6TG exposure. We demonstrate the efficacy of the genetic screen, investigate the phenotype of 26 MSH6 VUS and compare our screening results to clinical data from suspected-LS patients carrying these variant alleles.
PMID
Related Publications
Authors

Mayor MeshTerms
Keywords
Journal Title plos genetics
Publication Year Start




PMID- 28531214
OWN - NLM
STAT- Publisher
DA  - 20170522
LR  - 20170522
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Linking)
VI  - 13
IP  - 5
DP  - 2017 May 22
TI  - Suspected Lynch syndrome associated MSH6 variants: A functional assay to
      determine their pathogenicity.
PG  - e1006765
LID - 10.1371/journal.pgen.1006765 [doi]
AB  - Lynch syndrome (LS) is a hereditary cancer predisposition caused by inactivating 
      mutations in DNA mismatch repair (MMR) genes. Mutations in the MSH6 DNA MMR gene 
      account for approximately 18% of LS cases. Many LS-associated sequence variants
      are nonsense and frameshift mutations that clearly abrogate MMR activity.
      However, missense mutations whose functional implications are unclear are also
      frequently seen in suspected-LS patients. To conclusively diagnose LS and enroll 
      patients in appropriate surveillance programs to reduce morbidity as well as
      mortality, the functional consequences of these variants of uncertain clinical
      significance (VUS) must be defined. We present an oligonucleotide-directed
      mutagenesis screen for the identification of pathogenic MSH6 VUS. In the screen, 
      the MSH6 variant of interest is introduced into mouse embryonic stem cells by
      site-directed mutagenesis. Subsequent selection for MMR-deficient cells using the
      DNA damaging agent 6-thioguanine (6TG) allows the identification of MMR
      abrogating VUS because solely MMR-deficient cells survive 6TG exposure. We
      demonstrate the efficacy of the genetic screen, investigate the phenotype of 26
      MSH6 VUS and compare our screening results to clinical data from suspected-LS
      patients carrying these variant alleles.
FAU - Houlleberghs, Hellen
AU  - Houlleberghs H
AD  - Division of Biological Stress Response, The Netherlands Cancer Institute,
      Amsterdam, The Netherlands.
FAU - Goverde, Anne
AU  - Goverde A
AUID- ORCID: http://orcid.org/0000-0002-3238-4411
AD  - Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam,
      The Netherlands.
FAU - Lusseveld, Jarnick
AU  - Lusseveld J
AD  - Division of Biological Stress Response, The Netherlands Cancer Institute,
      Amsterdam, The Netherlands.
FAU - Dekker, Marleen
AU  - Dekker M
AUID- ORCID: http://orcid.org/0000-0001-8033-5692
AD  - Division of Biological Stress Response, The Netherlands Cancer Institute,
      Amsterdam, The Netherlands.
FAU - Bruno, Marco J
AU  - Bruno MJ
AD  - Department of Gastroenterology and Hepatology, Erasmus University Medical Center,
      Rotterdam, The Netherlands.
FAU - Menko, Fred H
AU  - Menko FH
AD  - Family Cancer Clinic, The Netherlands Cancer Institute, Amsterdam, The
      Netherlands.
FAU - Mensenkamp, Arjen R
AU  - Mensenkamp AR
AUID- ORCID: http://orcid.org/0000-0003-3805-877X
AD  - Department of Human Genetics, Radboud University Medical Center, Nijmegen, The
      Netherlands.
FAU - Spaander, Manon C W
AU  - Spaander MCW
AD  - Department of Gastroenterology and Hepatology, Erasmus University Medical Center,
      Rotterdam, The Netherlands.
FAU - Wagner, Anja
AU  - Wagner A
AD  - Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam,
      The Netherlands.
FAU - Hofstra, Robert M W
AU  - Hofstra RMW
AD  - Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam,
      The Netherlands.
FAU - Te Riele, Hein
AU  - Te Riele H
AUID- ORCID: http://orcid.org/0000-0003-0255-4042
AD  - Division of Biological Stress Response, The Netherlands Cancer Institute,
      Amsterdam, The Netherlands.
LA  - eng
PT  - Journal Article
DEP - 20170522
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
EDAT- 2017/05/23 06:00
MHDA- 2017/05/23 06:00
CRDT- 2017/05/23 06:00
PHST- 2016/11/16 [received]
PHST- 2017/04/18 [accepted]
AID - 10.1371/journal.pgen.1006765 [doi]
AID - PGENETICS-D-16-02553 [pii]
PST - aheadofprint
SO  - PLoS Genet. 2017 May 22;13(5):e1006765. doi: 10.1371/journal.pgen.1006765.

<?xml version="1.0" encoding="UTF-8"?>
<b:Sources SelectedStyle="" xmlns:b="http://schemas.openxmlformats.org/officeDocument/2006/bibliography"  xmlns="http://schemas.openxmlformats.org/officeDocument/2006/bibliography" >
</b:Sources>