A homozygous PMS2 founder mutation with an attenuated constitutional mismatch repair deficiency phenotype.
J Med Genet
; 52(5): 348-52, 2015 May.
Article
em En
| MEDLINE
| ID: mdl-25691505
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_000535.5c.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_000535.5c.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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenótipo
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Síndromes Neoplásicas Hereditárias
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Neoplasias Encefálicas
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Neoplasias Colorretais
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Adenosina Trifosfatases
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Efeito Fundador
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Enzimas Reparadoras do DNA
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Proteínas de Ligação a DNA
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Homozigoto
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Mutação
Tipo de estudo:
Prognostic_studies
Limite:
Adolescent
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Adult
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Aged
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Child
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Child, preschool
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Female
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Humans
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Infant
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article