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Mechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1.
Seo, Aaron; Steinberg-Shemer, Orna; Unal, Sule; Casadei, Silvia; Walsh, Tom; Gumruk, Fatma; Shalev, Stavit; Shimamura, Akiko; Akarsu, Nurten Ayse; Tamary, Hannah; King, Mary-Claire.
Afiliación
  • Seo A; Department of Medicine, University of Washington, Seattle, WA 98195.
  • Steinberg-Shemer O; Department of Genome Sciences, University of Washington, Seattle, WA 98195.
  • Unal S; Hematology Unit, Schneider Children's Medical Center, Petach Tikva 49202, Israel.
  • Casadei S; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
  • Walsh T; Department of Pediatrics, Hacettepe University, Ankara 06100, Turkey.
  • Gumruk F; Department of Medicine, University of Washington, Seattle, WA 98195.
  • Shalev S; Department of Genome Sciences, University of Washington, Seattle, WA 98195.
  • Shimamura A; Department of Medicine, University of Washington, Seattle, WA 98195.
  • Akarsu NA; Department of Genome Sciences, University of Washington, Seattle, WA 98195.
  • Tamary H; Department of Pediatric Hematology, Hacettepe University, Ankara 06100, Turkey.
  • King MC; Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3525433, Israel.
Proc Natl Acad Sci U S A ; 115(20): 5241-5246, 2018 05 15.
Article en En | MEDLINE | ID: mdl-29712865
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Neoplasias de la Mama / Empalme Alternativo / Codón sin Sentido / Proteína BRCA1 / Homocigoto Límite: Adolescent / Adult / Child / Child, preschool / Female / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Ováricas / Neoplasias de la Mama / Empalme Alternativo / Codón sin Sentido / Proteína BRCA1 / Homocigoto Límite: Adolescent / Adult / Child / Child, preschool / Female / Humans Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2018 Tipo del documento: Article Pais de publicación: Estados Unidos