Mechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1

Aaron Seo, Steinberg Shemer Orna, Sule Unal, Silvia Casadei, Tom Walsh, Fatma Gumruk, Stavit Shalev, Akiko Shimamura, Nurten Ayse Akarsu, Hannah Tamary, Mary Claire King*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Scopus citations


BRCA1 is essential for repair of DNA double-strand breaks by homologous recombination, and hence for survival. Complete loss of its function is lethal during early embryonic development. Patients who are compound heterozygous for BRCA1 truncating mutations and missense alleles that retain some DNA repair capacity may survive, albeit with very high risk of early onset breast or ovarian cancer and features of Fanconi anemia. However, a mechanism enabling survival of patients homozygous for BRCA1 truncating mutations has not been described. We studied two unrelated families in which four children presented with multiple congenital anomalies and severe chromosomal fragility. One child developed T cell acute lymphocytic leukemia (ALL), and a second child developed neuroblastoma. Each of the four children was homozygous for a nonsense mutation in BRCA1 exon 11. Homozygosity for the nonsense mutations was viable thanks to the presence of a naturally occurring alternative splice donor in BRCA1 exon 11 that lies 5′ of the mutations. The mutations did not affect the alternative splice site, but transcription from it produced an in-frame BRCA1 message with deletion of 3,309 bp. The translated BRCA1 protein was only 40% of normal length, but with intact N- and C-terminal sequences. These patients extend the range of BRCA1-related phenotypes and illustrate how naturally occurring alternative splicing can enable survival, albeit with severe consequences, of otherwise lethal genotypes of an essential gene.

Original languageEnglish
Pages (from-to)5241-5246
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number20
StatePublished - 15 May 2018


FundersFunder number
Turkish Ministry of Development2011K120020
National Institutes of HealthR35CA197458, F30DK103462
National Institute of Diabetes and Digestive and Kidney DiseasesR24DK099808
Breast Cancer Research Foundation
Türkiye Cumhuriyeti Disisleri Bakanligi


    • BRCA1
    • Chromosomal fragility
    • DNA repair
    • RNA splicing


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