Functional analysis of a duplication (p.E63_D69dup) in the switch II region of HRAS: new aspects of the molecular pathogenesis underlying Costello syndromeстатья из журнала
Аннотация: Costello syndrome is a congenital disorder comprising a characteristic face, severe feeding difficulties, skeletal, cardiac and skin abnormalities, intellectual disability and predisposition to malignancies. It is caused by heterozygous germline HRAS mutations mostly affecting Gly12 or Gly13, which impair HRAS-GTPase activity and result in increased downstream signal flow independent of incoming signals. Functional analyses of rarer HRAS mutations identified in individuals with attenuated Costello syndrome phenotypes revealed altered GDP/GTP nucleotide affinities (p.K117R) and inefficient effector binding (p.E37dup). Thus, both phenotypic and functional variability associated with HRAS mutations are evident. Here, we report on a novel heterozygous HRAS germline mutation (c.187_207dup, p.E63_D69dup) in a girl presenting with a phenotype at the milder end of the Costello syndrome spectrum. The p.E63_D69dup mutation impaired co-precipitation of recombinant HRAS with NF1 GTPase-activating protein (GAP) suggesting constitutive HRASE63_D69dup activation due to GAP insensitivity. Indeed, we identified strongly augmented active HRASE63_D69dup that co-precipitated with effectors RAF1, RAL guanine nucleotide dissociation stimulator and phospholipase C1. However, we could not pull down active HRASE63_D69dup using the target protein PIK3CA, indicating a compromised association between active HRASE63_D69dup and PIK3CA. Accordingly, overexpression of HRASE63_D69dup increased steady-state phosphorylation of MEK1/2 and ERK1/2 downstream of RAF, whereas AKT phosphorylation downstream of phosphoinositide 3-kinase (PI3K) was not enhanced. By analyzing signaling dynamics, we found that HRASE63_D69dup has impaired reagibility to stimuli resulting in reduced and disrupted capacity to transduce incoming signals to the RAF-MAPK and PI3K-AKT cascade, respectively. We suggest that disrupted HRAS reagibility, as we demonstrate for the p.E63_D69dup mutation, is a previously unappreciated molecular pathomechanism underlying Costello syndrome.
Год издания: 2013
Авторы: S. Lorenz, Christina Lißewski, Pelin Özlem Şimşek‐Kiper, Yasemin Alanay, Koray Boduroğlu, Martin Zenker, Georg Rosenberger
Издательство: Oxford University Press
Источник: Human Molecular Genetics
Ключевые слова: Protein Tyrosine Phosphatases, Protein Kinase Regulation and GTPase Signaling, PI3K/AKT/mTOR signaling in cancer
Другие ссылки: Human Molecular Genetics (HTML)
PubMed (HTML)
PubMed (HTML)
Открытый доступ: closed
Том: 22
Выпуск: 8
Страницы: 1643–1653