Developmental Syndromes of Ras/MAPK Pathway Dysregulation

Abstract

The term RASopathies designates a group of developmental syndromes caused by germline mutations in genes that encode proteins of the Ras/mitogen‐activated protein kinase (MAPK) signalling pathway. Ras/MAPK pathway controls several biological functions, such as cell proliferation, migration, differentiation and apoptosis. Similar molecular mechanisms disturbing the Ras/MAPK pathway were described in the RASopathies, including Noonan syndrome, Noonan syndrome with multiple lentigines, Noonan syndrome‐like disorder with loose anagen hair, CBL mutation‐associated syndrome, Costello syndrome, cardiofaciocutaneous syndrome, neurofibromatosis type 1 and Legius syndrome. Even though these syndromes share some overlapping features, genotype–phenotype correlations are well established for each of these, supporting the idea that they represent clinically distinct disorders. Owing to the similar mechanism encompassing Ras/MAPK germline and somatic mutations, Ras/MAPK pathway components have been considered a potential therapeutic target for RASopathies by promoting pathway modulation or small‐molecule inhibition.

Key Concepts:

  • Ras/MAPK is one of the most well‐known signalling pathways and plays an important role in critical cellular functions to normal development.

  • RASopathies are a group of medical genetic disorders caused by gain‐of‐function germline mutations in components of the Ras/MAPK signalling pathway.

  • Although the RASopathies may share clinically overlapping features, they also exhibit some individual ones that support the concept that they are distinct disorders.

  • Ras/MAPK germline mutations are similar to somatic mutations when associated with cancer, but they tend to be weakly activating.

  • Noonan syndrome is a frequent autosomal dominant disorder characterised by facial dysmorphisms, heart defects, short stature and learning disabilities.

  • The best clinical practice for each RASopathy could be defined if its genotype–phenotype correlation is understood.

Keywords: cardiofaciocutaneous syndrome; Costello syndrome; Legius syndrome; LEOPARD syndrome; neurofibromatosis; Noonan syndrome; Ras/MAPK; RASopathies; signal transduction pathway

Figure 1.

Ras/MAPK pathway. After the binding of a growth factor to RTKs, there is an autophosphorylation of tyrosine sites within receptor and recruitment of adaptor proteins, such as GRB2 and SOS1, which acts in stimulating the switch from inactive Ras‐GDP to active Ras‐GTP. The Ras‐GTP recruits Raf to the plasma membrane by phosphorylation of Raf isoforms at numerous residues. Once activated, Raf isoforms bind and phosphorylate MEK1/2, which, in turn, phosphorylate and activate ERK1/2. ERK1/2 are the ultimate effectors of the MAPK pathway and exert their function on a large number of downstream molecules, including transcription factors, membrane proteins and protein kinases, which, in turn, control vital cellular functions. NF1 and SPRED1 are negative regulators of Ras/MAPK signalling pathway. SHOC2 is important to the translocation of Raf isoforms to plasma membrane. CBL mediates the association of ubiquitin with activated RTK, which is necessary for receptor internalisation and degradation.

Figure 2.

NS features: (a) eye abnormalities: ptosis, hypertelorism, downslanting palpebral fissures and epicanthal fold; (b) ear abnormalities: low‐set posteriorly rotated ears with thick helices; (c) short and webbed neck and a low posterior hairline and (d) chest deformities: pectus carinatum superiorly and pectus excavatum inferiorly.

Figure 3.

(a) Cardiofaciocutaneous syndrome typical ulerythema ophryogenes (absent eyebrows with hyperkeratosis); (b) Deep palmar and plantar creases and (c) Generalised multiple lentigines in a patient with NS with multiple lentigines/Leopard syndrome.

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Further Reading

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Malaquias, Alexsandra C, and Jorge, Alexander AL(Mar 2014) Developmental Syndromes of Ras/MAPK Pathway Dysregulation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0021426]