Open AccessMechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1
Author(s) -
Aaron Seo,
Orna SteinbergShemer,
Şule Ünal,
Silvia Casadei,
Tom Walsh,
Fatma Gümrük,
Stavit A. Shalev,
Akiko Shimamura,
Nurten Akarsu,
Hannah Tamary,
MaryClaire King
Publication year - 2018
Publication title -
proceedings of the national academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.1801796115
Subject(s) - nonsense mutation , genetics , biology , nonsense , mutation , gene , suppressor , cancer research , tumor suppressor gene , ovarian cancer , cancer , rna splicing , loss function , missense mutation , carcinogenesis , phenotype , rna
Significance Many patients with breast and ovarian cancer carry inherited cancer-predisposing mutations inBRCA1 . However, virtually no patients have two inherited mutations inBRCA1 because the DNA repair function ofBRCA1 is essential for embryonic development. We discovered that patients with two nonsense mutations from a specific region ofBRCA1 may survive as the result of naturally occurring alternative splicing that yields a short but partially functional BRCA1 protein. These patients are extremely rare, and are characterized by severe chromosomal fragility, congenital anomalies, and predisposition to childhood cancers.
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