Genotype and phenotype spectrum of NRAS germline variants
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Citações na Scopus
36
Tipo de produção
article
Data de publicação
2017
Título da Revista
ISSN da Revista
Título do Volume
Editora
NATURE PUBLISHING GROUP
Autores
ALTMUELLER, Franziska
LISSEWSKI, Christina
FLEX, Elisabetta
STARK, Zornitza
SPRANGER, Stephanie
BAYNAM, Gareth
DYACK, Sarah
GILLIS, Jane
Citação
EUROPEAN JOURNAL OF HUMAN GENETICS, v.25, n.7, p.823-831, 2017
Resumo
RASopathies comprise a group of disorders clinically characterized by short stature, heart defects, facial dysmorphism, and varying degrees of intellectual disability and cancer predisposition. They are caused by germline variants in genes encoding key components or modulators of the highly conserved RAS-MAPK signalling pathway that lead to dysregulation of cell signal transmission. Germline changes in the genes encoding members of the RAS subfamily of GTPases are rare and associated with variable phenotypes of the RASopathy spectrum, ranging from Costello syndrome (HRAS variants) to Noonan and Cardiofaciocutaneous syndromes (KRAS variants). A small number of RASopathy cases with disease-causing germline NRAS alterations have been reported. Affected individuals exhibited features fitting Noonan syndrome, and the observed germline variants differed from the typical oncogenic NRAS changes occurring as somatic events in tumours. Here we describe 19 new cases with RASopathy due to disease-causing variants in NRAS. Importantly, four of them harbored missense changes affecting Gly12, which was previously described to occur exclusively in cancer. The phenotype in our cohort was variable but well within the RASopathy spectrum. Further, one of the patients (c. 35G > A; p.(Gly12Asp)) had a myeloproliferative disorder, and one subject (c. 34G > C; p.(Gly12Arg)) exhibited an uncharacterized brain tumour. With this report, we expand the genotype and phenotype spectrum of RASopathy-associated germline NRAS variants and provide evidence that NRAS variants do not spare the cancer-associated mutation hotspots.
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Referências
- Ahmadian MR, 1999, P NATL ACAD SCI USA, V96, P7065, DOI 10.1073/pnas.96.12.7065
- Aoki Y, 2005, NAT GENET, V37, P1038, DOI 10.1038/ng1641
- Aoki Y, 2013, AM J HUM GENET, V93, P173, DOI 10.1016/j.ajhg.2013.05.021
- BARBACID M, 1987, ANNU REV BIOCHEM, V56, P779, DOI 10.1146/annurev.bi.56.070187.004023
- BOS JL, 1989, CANCER RES, V49, P4682
- Caye A, 2015, NAT GENET, V47, P1334, DOI 10.1038/ng.3420
- Chang JZ, 2015, GENE, V569, P46, DOI 10.1016/j.gene.2015.04.090
- Cirstea IC, 2010, NAT GENET, V42, P27, DOI 10.1038/ng.497
- Coppinger J, 2009, HUM MOL GENET, V18, P1377, DOI 10.1093/hmg/ddp042
- Cordeddu V, 2015, HUM MUTAT, V36, P1080, DOI 10.1002/humu.22834
- Cordeddu V, 2009, NAT GENET, V41, P1022, DOI 10.1038/ng.425
- De Filippi P, 2009, BRIT J HAEMATOL, V147, P706, DOI 10.1111/j.1365-2141.2009.07894.x
- Denayer E, 2012, MOL SYNDROMOL, V3, P34, DOI 10.1159/000338467
- Digilio M C, 2011, Mol Syndromol, V1, P282
- Ekvall S, 2015, BMC MED GENET, V16, DOI 10.1186/s12881-015-0239-1
- Estep AL, 2006, AM J MED GENET A, V140A, P8, DOI 10.1002/ajmg.a.31078
- FASANO O, 1984, P NATL ACAD SCI-BIOL, V81, P4008, DOI 10.1073/pnas.81.13.4008
- Flex E, 2014, HUM MOL GENET, V23, P4315, DOI 10.1093/hmg/ddu148
- Forbes SA, 2015, NUCLEIC ACIDS RES, V43, pD805, DOI 10.1093/nar/gku1075
- Gremer L, 2011, HUM MUTAT, V32, P33, DOI 10.1002/humu.21377
- Gremer L, 2010, HUM MOL GENET, V19, P790, DOI 10.1093/hmg/ddp548
- Gripp KW, 2016, AM J MED GENET A, V170, P2237, DOI 10.1002/ajmg.a.37781
- Gripp KW, 2005, AM J MED GENET C, V137C, P72, DOI 10.1002/ajmg.c.30065
- Hafner C, 2012, J MED GENET, V49, P249, DOI 10.1136/jmedgenet-2011-100637
- Hennekam RCM, 2003, AM J MED GENET C, V117C, P42, DOI 10.1002/ajmg.c.10019
- Hiramoto R, 2015, INT J HEMATOL, V102, P719, DOI 10.1007/s12185-015-1877-y
- Imanishi D, 2007, BLOOD, V110, P2231, DOI 10.1182/blood-2007-02-071423
- Karnoub AE, 2008, NAT REV MOL CELL BIO, V9, P517, DOI 10.1038/nrm2438
- Kraoua L, 2012, AM J MED GENET A, V158A, P2407, DOI 10.1002/ajmg.a.35513
- Kratz CP, 2015, BRIT J CANCER, V112, P1392, DOI 10.1038/bjc.2015.75
- Kratz CP, 2005, BLOOD, V106, P2183, DOI 10.1182/blood-2005-02-0531
- Lorenz S, 2012, EUR J MED GENET, V55, P615, DOI 10.1016/j.ejmg.2012.07.007
- Marino B, 1999, J PEDIATR-US, V135, P703, DOI 10.1016/S0022-3476(99)70088-0
- Martinelli S, 2010, AM J HUM GENET, V87, P250, DOI 10.1016/j.ajhg.2010.06.015
- Nava C, 2007, J MED GENET, V44, P763, DOI 10.1136/jmg.2007.050450
- Niemeyer Charlotte M, 2014, Haematologica, V99, P1653, DOI 10.3324/haematol.2014.114595
- Oliveira JB, 2007, P NATL ACAD SCI USA, V104, P8953, DOI 10.1073/pnas.0702975104
- Perez B, 2010, J MED GENET, V47, P686, DOI 10.1136/jmg.2010.076836
- Rauen KA, 2013, ANNU REV GENOM HUM G, V14, P355, DOI 10.1146/annurev-genom-091212-153523
- Roberts A, 2006, J MED GENET, V43, P833, DOI 10.1136/jmg.2006.042796
- Roberts AE, 2013, LANCET, V381, P333, DOI 10.1016/S0140-6736(12)61023-X
- Runtuwene V, 2011, DIS MODEL MECH, V4, P393, DOI 10.1242/dmm.007112
- Sarkozy A, 2009, HUM MUTAT, V30, P695, DOI 10.1002/humu.20955
- Schubbert S, 2006, NAT GENET, V38, P331, DOI 10.1038/ng1748
- Stieglitz E, 2015, NAT GENET, V47, P1326, DOI 10.1038/ng.3400
- Strullu M, 2014, J MED GENET, V51, P689, DOI 10.1136/jmedgenet-2014-102611
- Tartaglia M, 2011, CLIN ENDOCRINOL META, V25, P161
- Tartaglia M, 2010, ANN NY ACAD SCI, V1214, P99, DOI 10.1111/j.1749-6632.2010.05790.x
- Wey M, 2013, BIOCHEMISTRY-US, V52, P8465, DOI 10.1021/bi400679q
- Yamamoto GL, 2015, J MED GENET, V52, P413, DOI 10.1136/jmedgenet-2015-103018
- Zenker M, 2007, J MED GENET, V44, P131, DOI 10.1136/jmg.2006.046300
- Zenker M, 2011, CURR OPIN PEDIATR, V23, P443, DOI 10.1097/MOP.0b013e32834881dd