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J Med Genet. 2015 May;52(5):348-52. doi: 10.1136/jmedgenet-2014-102934. Epub 2015 Feb 17.

A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype.

Author information

1
Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
2
Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada.
3
Department of Pathology, McGill University, Montreal, Quebec, Canada Gastroenterology Division, Brigham and Women's Hospital, Boston, Massachusetts, USA.
4
Department of Software and Information Technology Engineering, École de technologie supérieure, Montreal, Quebec, Canada.
5
Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.
6
Department of Pathology, Jewish General Hospital, Montreal, Quebec, Canada.
7
Department of Pathology, McGill University Health Centre, Montreal, Quebec, Canada.
8
Department of Pediatrics and Child Health and Department of Biochemistry and Medical Genetics, Winnipeg, Manitoba, Canada.
9
Department of Pathology, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.
10
INSERM U768, Hôpital Necker, Paris, France.
11
Robarts Research Institute and Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada.
12
Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.
13
Systems Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
14
Department of Molecular Medicine and Medical Biotechnology and CEINGE Biotechnologie Avanzate, University of Naples-Federico II, Naples, Italy.
15
USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
16
Division Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University Innsbruck, Innsbruck, Austria.
17
Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada First Nations and Inuit Health Branch, Health Canada (Quebec Region), Montreal, Quebec, Canada.
18
Department of Human Genetics, McGill University, Montreal, Quebec, Canada Department of Pathology, Jewish General Hospital, Montreal, Quebec, Canada.
19
Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada Department of Human Genetics, McGill University, Montreal, Quebec, Canada Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada Department of Medical Genetics, University of Cambridge, Cambridge, UK.
20
Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada Department of Human Genetics, McGill University, Montreal, Quebec, Canada Department of Medical Genetics, McGill University Health Centre, Montreal, Quebec, Canada Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.

Abstract

BACKGROUND:

Inherited mutations in DNA mismatch repair genes predispose to different cancer syndromes depending on whether they are mono-allelic or bi-allelic. This supports a causal relationship between expression level in the germline and phenotype variation. As a model to study this relationship, our study aimed to define the pathogenic characteristics of a recurrent homozygous coding variant in PMS2 displaying an attenuated phenotype identified by clinical genetic testing in seven Inuit families from Northern Quebec.

METHODS:

Pathogenic characteristics of the PMS2 mutation NM_000535.5:c.2002A>G were studied using genotype-phenotype correlation, single-molecule expression detection and single genome microsatellite instability analysis.

RESULTS:

This PMS2 mutation generates a de novo splice site that competes with the authentic site. In homozygotes, expression of the full-length protein is reduced to a level barely detectable by conventional diagnostics. Median age at primary cancer diagnosis is 22 years among 13 NM_000535.5:c.2002A>G homozygotes, versus 8 years in individuals carrying bi-allelic truncating mutations. Residual expression of full-length PMS2 transcript was detected in normal tissues from homozygotes with cancers in their 20s.

CONCLUSIONS:

Our genotype-phenotype study of c.2002A>G illustrates that an extremely low level of PMS2 expression likely delays cancer onset, a feature that could be exploited in cancer preventive intervention.

KEYWORDS:

constitutional mismatch repair deficiency (CMMRD); gene expression; genotype-phenotype; splice site; tumor suppression

PMID:
25691505
DOI:
10.1136/jmedgenet-2014-102934
[Indexed for MEDLINE]

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