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Activating mutation...
Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis
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Flex, Elisabetta (author)
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Jaiswal, Mamta (author)
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Pantaleoni, Francesca (author)
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Martinelli, Simone (author)
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Strullu, Marion (author)
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Fansa, Eyad K (author)
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Caye, Aurélie (author)
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De Luca, Alessandro (author)
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Lepri, Francesca (author)
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Dvorsky, Radovan (author)
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Pannone, Luca (author)
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Paolacci, Stefano (author)
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Zhang, Si-Cai (author)
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Fodale, Valentina (author)
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Bocchinfuso, Gianfranco (author)
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Rossi, Cesare (author)
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Burkitt-Wright, Emma M M (author)
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Farrotti, Andrea (author)
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Stellacci, Emilia (author)
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Cecchetti, Serena (author)
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Ferese, Rosangela (author)
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Bottero, Lisabianca (author)
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Castro, Silvana (author)
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Fenneteau, Odile (author)
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Brethon, Benoit (author)
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Sanchez, Massimo (author)
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Roberts, Amy E (author)
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Yntema, Helger G (author)
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Van Der Burgt, Ineke (author)
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Cianci, Paola (author)
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- Bondeson, Marie-Louise (author)
- Uppsala universitet,Medicinsk genetik,Bondeson/Anneren
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Cristina Digilio, Maria (author)
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Zampino, Giuseppe (author)
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Kerr, Bronwyn (author)
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Aoki, Yoko (author)
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Loh, Mignon L (author)
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Palleschi, Antonio (author)
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Di Schiavi, Elia (author)
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Carè, Alessandra (author)
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Selicorni, Angelo (author)
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Dallapiccola, Bruno (author)
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Cirstea, Ion C (author)
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Stella, Lorenzo (author)
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Zenker, Martin (author)
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Gelb, Bruce D (author)
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Cavé, Hélène (author)
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Ahmadian, Mohammad R (author)
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Tartaglia, Marco (author)
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(creator_code:org_t)
- 2014-04-04
- 2014
- English.
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:16, s. 4315-4327
- Related links:
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https://academic.oup...
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Subject headings
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- RASopathies, a family of disorders characterized by cardiac defects, defective growth, facial dysmorphism, variable cognitive deficits and predisposition to certain malignancies, are caused by constitutional dysregulation of RAS signalling predominantly through the RAF/MEK/ERK (MAPK) cascade. We report on two germline mutations (p.Gly39dup and p.Val55Met) in RRAS, a gene encoding a small monomeric GTPase controlling cell adhesion, spreading and migration, underlying a rare (2 subjects among 504 individuals analysed) and variable phenotype with features partially overlapping Noonan syndrome, the most common RASopathy. We also identified somatic RRAS mutations (p.Gly39dup and p.Gln87Leu) in 2 of 110 cases of non-syndromic juvenile myelomonocytic leukaemia, a childhood myeloproliferative/myelodysplastic disease caused by upregulated RAS signalling, defining an atypical form of this haematological disorder rapidly progressing to acute myeloid leukaemia. Two of the three identified mutations affected known oncogenic hotspots of RAS genes and conferred variably enhanced RRAS function and stimulus-dependent MAPK activation. Expression of an RRAS mutant homolog in Caenorhabditis elegans enhanced RAS signalling and engendered protruding vulva, a phenotype previously linked to the RASopathy-causing SHOC2(S2G) mutant. Overall, these findings provide evidence of a functional link between RRAS and MAPK signalling and reveal an unpredicted role of enhanced RRAS function in human disease.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
- NATURVETENSKAP -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Flex, Elisabetta
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Jaiswal, Mamta
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Pantaleoni, Fran ...
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Martinelli, Simo ...
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Strullu, Marion
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Fansa, Eyad K
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show more...
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Caye, Aurélie
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De Luca, Alessan ...
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Lepri, Francesca
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Dvorsky, Radovan
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Pannone, Luca
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Paolacci, Stefan ...
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Zhang, Si-Cai
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Fodale, Valentin ...
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Bocchinfuso, Gia ...
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Rossi, Cesare
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Burkitt-Wright, ...
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Farrotti, Andrea
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Stellacci, Emili ...
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Cecchetti, Seren ...
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Ferese, Rosangel ...
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Bottero, Lisabia ...
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Castro, Silvana
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Fenneteau, Odile
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Brethon, Benoit
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Sanchez, Massimo
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Roberts, Amy E
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Yntema, Helger G
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Van Der Burgt, I ...
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Cianci, Paola
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Bondeson, Marie- ...
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Cristina Digilio ...
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Zampino, Giusepp ...
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Kerr, Bronwyn
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Aoki, Yoko
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Loh, Mignon L
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Palleschi, Anton ...
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Di Schiavi, Elia
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Carè, Alessandra
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Selicorni, Angel ...
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Dallapiccola, Br ...
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Cirstea, Ion C
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Stella, Lorenzo
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Zenker, Martin
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Gelb, Bruce D
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Cavé, Hélène
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Ahmadian, Mohamm ...
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Tartaglia, Marco
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Medical Genetics
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- NATURAL SCIENCES
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NATURAL SCIENCES
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and Biological Scien ...
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and Biochemistry and ...
- Articles in the publication
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Human Molecular ...
- By the university
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Uppsala University