The RASopathies: from Pathogenetics to Therapeutics

Overview

Journal Dis Model Mech

Specialty General Medicine

Date 2022 Feb 18

PMID 35178568

Authors

Katie E Hebron

Edjay Ralph Hernandez

Marielle E Yohe

Affiliations

Soon will be listed here.

Abstract

The RASopathies are a group of disorders caused by a germline mutation in one of the genes encoding a component of the RAS/MAPK pathway. These disorders, including neurofibromatosis type 1, Noonan syndrome, cardiofaciocutaneous syndrome, Costello syndrome and Legius syndrome, among others, have overlapping clinical features due to RAS/MAPK dysfunction. Although several of the RASopathies are very rare, collectively, these disorders are relatively common. In this Review, we discuss the pathogenesis of the RASopathy-associated genetic variants and the knowledge gained about RAS/MAPK signaling that resulted from studying RASopathies. We also describe the cell and animal models of the RASopathies and explore emerging RASopathy genes. Preclinical and clinical experiences with targeted agents as therapeutics for RASopathies are also discussed. Finally, we review how the recently developed drugs targeting RAS/MAPK-driven malignancies, such as inhibitors of RAS activation, direct RAS inhibitors and RAS/MAPK pathway inhibitors, might be leveraged for patients with RASopathies.

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References

Borrie S, Plasschaert E, Callaerts-Vegh Z, Yoshimura A, DHooge R, Elgersma Y . MEK inhibition ameliorates social behavior phenotypes in a Spred1 knockout mouse model for RASopathy disorders. Mol Autism. 2021; 12(1):53. PMC: 8314535. DOI: 10.1186/s13229-021-00458-2. View

Williams K, Largaespada D . New Model Systems and the Development of Targeted Therapies for the Treatment of Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors. Genes (Basel). 2020; 11(5). PMC: 7290716. DOI: 10.3390/genes11050477. View

Pages G, Guerin S, Grall D, Bonino F, Smith A, Anjuere F . Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science. 1999; 286(5443):1374-7. DOI: 10.1126/science.286.5443.1374. View

Motta M, Fidan M, Bellacchio E, Pantaleoni F, Schneider-Heieck K, Coppola S . Dominant Noonan syndrome-causing LZTR1 mutations specifically affect the Kelch domain substrate-recognition surface and enhance RAS-MAPK signaling. Hum Mol Genet. 2018; 28(6):1007-1022. DOI: 10.1093/hmg/ddy412. View

Cordeddu V, Di Schiavi E, Pennacchio L, Maayan A, Sarkozy A, Fodale V . Mutation of SHOC2 promotes aberrant protein N-myristoylation and causes Noonan-like syndrome with loose anagen hair. Nat Genet. 2009; 41(9):1022-6. PMC: 2765465. DOI: 10.1038/ng.425. View

Borrie S, Horner A, Yoshimura A, Legius E, Kopanitsa M, Brems H . Impaired instrumental learning in Spred1 mice, a model for a rare RASopathy. Genes Brain Behav. 2021; 20(5):e12727. DOI: 10.1111/gbb.12727. View

Brems H, Pasmant E, van Minkelen R, Wimmer K, Upadhyaya M, Legius E . Review and update of SPRED1 mutations causing Legius syndrome. Hum Mutat. 2012; 33(11):1538-46. DOI: 10.1002/humu.22152. View

Denayer E, Peeters H, Sevenants L, Derbent M, Fryns J, Legius E . NRAS Mutations in Noonan Syndrome. Mol Syndromol. 2012; 3(1):34-38. PMC: 3398822. DOI: 10.1159/000338467. View

Josowitz R, Mulero-Navarro S, Rodriguez N, Falce C, Cohen N, Ullian E . Autonomous and Non-autonomous Defects Underlie Hypertrophic Cardiomyopathy in BRAF-Mutant hiPSC-Derived Cardiomyocytes. Stem Cell Reports. 2016; 7(3):355-369. PMC: 5032183. DOI: 10.1016/j.stemcr.2016.07.018. View

10.

Kent O, Saha M, Coyaud E, Burston H, Law N, Dadson K . Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes. Nat Commun. 2020; 11(1):4673. PMC: 7495420. DOI: 10.1038/s41467-020-18483-9. View

11.

Vaseva A, Yohe M . Targeting RAS in pediatric cancer: is it becoming a reality?. Curr Opin Pediatr. 2019; 32(1):48-56. PMC: 9422199. DOI: 10.1097/MOP.0000000000000856. View

12.

Inoue H, Kato R, Fukuyama S, Nonami A, Taniguchi K, Matsumoto K . Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness. J Exp Med. 2005; 201(1):73-82. PMC: 2212755. DOI: 10.1084/jem.20040616. View

13.

Gripp K, Lin A, Stabley D, Nicholson L, Scott Jr C, Doyle D . HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A. 2005; 140(1):1-7. DOI: 10.1002/ajmg.a.31047. View

14.

Marin T, Keith K, Davies B, Conner D, Guha P, Kalaitzidis D . Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest. 2011; 121(3):1026-43. PMC: 3049377. DOI: 10.1172/JCI44972. View

15.

Oba D, Inoue S, Miyagawa-Tomita S, Nakashima Y, Niihori T, Yamaguchi S . Mice with an Oncogenic HRAS Mutation are Resistant to High-Fat Diet-Induced Obesity and Exhibit Impaired Hepatic Energy Homeostasis. EBioMedicine. 2017; 27:138-150. PMC: 5828294. DOI: 10.1016/j.ebiom.2017.11.029. View

16.

Bigenzahn J, Collu G, Kartnig F, Pieraks M, Vladimer G, Heinz L . LZTR1 is a regulator of RAS ubiquitination and signaling. Science. 2018; 362(6419):1171-1177. PMC: 6794158. DOI: 10.1126/science.aap8210. View

17.

Sevick-Muraca E, King P . Lymphatic vessel abnormalities arising from disorders of Ras signal transduction. Trends Cardiovasc Med. 2013; 24(3):121-7. PMC: 3943571. DOI: 10.1016/j.tcm.2013.09.004. View

18.

Cirstea I, Kutsche K, Dvorsky R, Gremer L, Carta C, Horn D . A restricted spectrum of NRAS mutations causes Noonan syndrome. Nat Genet. 2009; 42(1):27-9. PMC: 3118669. DOI: 10.1038/ng.497. View

19.

Monaco K, Delach S, Yuan J, Mishina Y, Fordjour P, Labrot E . LXH254, a Potent and Selective ARAF-Sparing Inhibitor of BRAF and CRAF for the Treatment of MAPK-Driven Tumors. Clin Cancer Res. 2020; 27(7):2061-2073. DOI: 10.1158/1078-0432.CCR-20-2563. View

20.

Parker M, Fryer A, Shears D, Lachlan K, McKee S, Magee A . De novo, heterozygous, loss-of-function mutations in SYNGAP1 cause a syndromic form of intellectual disability. Am J Med Genet A. 2015; 167A(10):2231-7. PMC: 4744742. DOI: 10.1002/ajmg.a.37189. View