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Costello syndrome (CS) may be caused by activating mutations in codon 12/13 of the HRAS proto-oncogene. HRAS p.Gly12Val mutations have the highest transforming activity, are very frequent in cancers, but very rare in CS, where they are reported to cause a severe, early lethal, phenotype. We identified an unusual, new germline p.Gly12Val mutation, c.35_36GC>TG, in a 12-year-old boy with attenuated CS. Analysis of his HRAS cDNA showed high levels of exon 2 skipping. Using wild type and mutant HRAS minigenes, we confirmed that c.35_36GC>TG results in exon 2 skipping by simultaneously disrupting the function of a critical Exonic Splicing Enhancer (ESE) and creation of an Exonic Splicing Silencer (ESS). We show that this vulnerability of HRAS exon 2 is caused by a weak 3' splice site, which makes exon 2 inclusion dependent on binding of splicing stimulatory proteins, like SRSF2, to the critical ESE. Because the majority of cancer- and CS- causing mutations are located here, they affect splicing differently. Therefore, our results also demonstrate that the phenotype in CS and somatic cancers is not only determined by the different transforming potentials of mutant HRAS proteins, but also by the efficiency of exon 2 inclusion resulting from the different HRAS mutations. Finally, we show that a splice switching oligonucleotide (SSO) that blocks access to the critical ESE causes exon 2 skipping and halts proliferation of cancer cells. This unravels a potential for development of new anti-cancer therapies based on SSO-mediated HRAS exon 2 skipping.
Pubmed ID: 27195699 RIS Download
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The mission of the Doris Duke Charitable Foundation is to improve the quality of people''s lives through grants supporting the performing arts, environmental conservation, medical research and the prevention of child abuse, and through preservation of the cultural and environmental legacy of Doris Duke''s properties. Established in 1996, the foundation supports four national grant-making programs. It also supports three properties that were owned by Doris Duke in Hillsborough, New Jersey; Honolulu, Hawaii; and Newport, Rhode Island. The foundation is headquartered in New York and is governed by a board of 12 Trustees. DDCF''s activities are guided by the will of Doris Duke, who endowed the foundation with financial assets that totaled approximately $1.6 billion as of December 31, 2010. The foundation regularly evaluates and modifies its allocation of resources from the endowment to support the programs and properties and to respond to fluctuations in portfolio returns. The foundation awarded its first grants in 1997. As of December 31, 2011, the foundation has awarded grants totaling more than $1 billion. DDCF awards grants in four core program areas: * The Arts Program supports performing artists with the creation and public performance of their work. * The Environment Program supports efforts that enable communities to protect and manage wildlife habitat and create efficient built environments. * The Medical Research Program seeks to contribute to the prevention and cure of disease by supporting clinical research. * The Child Abuse Prevention Program seeks to protect children from abuse and neglect in order to promote their healthy development. In the fall of 2007, DDCF also launched the African Health Initiative, with the goal of strengthening health systems in sub-Saharan Africa. The Building Bridges Program, which seeks to increase public understanding of Islamic cultures through media and the arts, is funded through the Doris Duke Foundation for Islamic Art and is headquartered in DDCF''s offices in New York. The Properties In her will, Doris Duke requested that several operating foundations manage the properties listed below. She also expressed her wishes that the properties be opened for public visitation and used for educational programs. The operating foundations receive funding from the Doris Duke Charitable Foundation. * The Duke Farms Foundation manages a 2,700-acre property in Hillsborough, New Jersey, which is known as Duke Farms and has a mission of environmental stewardship. * The Doris Duke Foundation for Islamic Art manages Doris Duke''s home in Honolulu, Hawaii, which is known as Shangri La and serves as a center for the study of Islamic art and cultures. * The Newport Restoration Foundation preserves historic houses in Newport, Rhode Island, and operates Doris Duke''s home in Newport known as Rough Point, which is also a public museum.
View all literature mentionsCell line Hep-G2 is a Cancer cell line with a species of origin Homo sapiens (Human)
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