Dataset Information

Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis.

ABSTRACT: 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.

SUBMITTER: Flex E

PROVIDER: S-EPMC4103678 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis.

Flex Elisabetta E Jaiswal Mamta M Pantaleoni Francesca F Martinelli Simone S Strullu Marion M Fansa Eyad K EK Caye Aurélie A De Luca Alessandro A Lepri Francesca F Dvorsky Radovan R Pannone Luca L Paolacci Stefano S Zhang Si-Cai SC Fodale Valentina V Bocchinfuso Gianfranco G Rossi Cesare C Burkitt-Wright Emma M M EM Farrotti Andrea A Stellacci Emilia E Cecchetti Serena S Ferese Rosangela R Bottero Lisabianca L Castro Silvana S Fenneteau Odile O Brethon Benoît B Sanchez Massimo M Roberts Amy E AE Yntema Helger G HG Van Der Burgt Ineke I Cianci Paola P Bondeson Marie-Louise ML Cristina Digilio Maria M Zampino Giuseppe G Kerr Bronwyn B Aoki Yoko Y Loh Mignon L ML Palleschi Antonio A Di Schiavi Elia E Carè Alessandra A Selicorni Angelo A Dallapiccola Bruno B Cirstea Ion C IC Stella Lorenzo L Zenker Martin M Gelb Bruce D BD Cavé Hélène H Ahmadian Mohammad R MR Tartaglia Marco M

Human molecular genetics 20140404 16

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 ...[more]

PMID: 24705357

Similar Datasets

Project description:Purpose:To describe the mutation spectrum of SPATA7 and associated ocular phenotypes. Methods:As part of a continuing examination of the genetic basis of inherited ophthalmic diseases, sequencing variations in SPATA7 were identified in sequencing data from 5,090 probands. Mutations in SPATA7 were identified in 12 Chinese patients from ten families. Family history and clinical data were examined in detail in these patients. To evaluate possible gene-specific fundus changes, the results were combined with data from 66 patients from 50 families previously reported in the literature. Results:Seven homozygous or compound heterozygous mutations, including two novel mutations (c.367C>T, p.Q123* and c.1083-2A>G) and five known mutations in SPATA7, were identified in ten families, including six families with Leber congenital amaurosis (LCA), three families with juvenile retinitis pigmentosa, and one family with early-onset high myopia. These families accounted for approximately 2.2% (6/269) of LCA and 0.4% (10/2,252) of inherited retinal dystrophies in this case series. A combined analysis of data from the present study and data from 60 families reported in the literature showed that 93.3% (112/120) of mutant alleles were truncation mutations, whereas only about 5.0% were missense mutations, and 1.7% were non-frameshift indels. Common SPATA7-associated fundus changes, including narrow arterioles, a relatively well-preserved macular region, and widespread RPE atrophy resulting in diffuse mottled hypopigmentation in the midperipheral retina, were identified in this cohort and in patients in the literature. Missense mutations were not associated with specific phenotypic features or severity. Conclusions:Narrow arterioles, a relatively well-preserved macular region, and widespread RPE atrophy resulting in diffuse mottling hypopigmentation in the midperipheral retina may be considered early and common fundus changes specific to SPATA7-associated retinopathy. The fact that similar mutations result in varied phenotypes points to the existence of other potential modifiers of the disease. Uncovering the identity of these modifiers might aid the development of novel treatments.

Dataset Information

Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis.

Publications

Activating mutations in RRAS underlie a phenotype within the RASopathy spectrum and contribute to leukaemogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets