The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation

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The Ras/mitogen activated protein kinase (MAPK) pathway is essential in the regulation of the cell cycle, differentiation, growth and cell senescence, all of which are critical to normal development. It is therefore not surprising that its dysregulation has profound effects on development. A class of developmental syndromes, the ‘RASopathies’, is caused by germline mutations in genes that encode protein components of the Ras/MAPK pathway. The vast majority of these mutations result in increased signal transduction down the Ras/MAPK pathway, but usually to a lesser extent than somatic mutations associated with oncogenesis. Each syndrome exhibits unique phenotypic features, however, since they all cause dysregulation of the Ras/MAPK pathway, there are numerous overlapping phenotypic features between the syndromes, including characteristic facial features, cardiac defects, cutaneous abnormalities, neurocognitive delay and a predisposition to malignancies. Here we review the clinical and underlying molecular basis for each of these syndromes.

Introduction

A class of human genetic syndromes has emerged that are caused by germline mutations in genes which encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway. This pathway plays an essential role in the control of the cell cycle and differentiation, therefore its dysregulation has profound developmental consequences. These ‘RASopathies’ each exhibit unique phenotypic features, however, many share characteristic overlapping features including craniofacial dysmorphology, cardiac malformations and cutaneous, musculoskeletal and ocular abnormalities, varying degrees of neurocognitive impairment and, in some syndromes, an increased risk of developing cancer.

The Ras/MAPK pathway transduces extracellular input in the form of growth factors and small molecules to the intracellular environment (Figure 1). The pathway has been studied extensively in the context of oncogenesis since its dysregulation is one of the primary causes of cancer, with Ras found to be somatically mutated in approximately 20% of malignancies [1]. Ras proteins are small guanosine nucleotide-bound GTPases which comprise a critical signaling hub within the cell. Ras genes exist as a multigene family that includes HRAS, NRAS and KRAS. They are activated through growth factors binding to receptor tyrosine kinases (RTK), G-protein-coupled receptors, cytokine receptors and extracellular matrix receptors. Ras proteins cycle between an active GTP-bound form and an inactive GDP-bound form. Activation through RTK occurs with the binding of a growth factor causing RTK autophosphorylation and interaction with the adaptor protein GRB2. GRB2 is bound to SOS which is then recruited to the plasma membrane. SOS proteins are guanosine nucleotide exchange factors (GEF) that increase the Ras nucleotide exchange rate of GDP for GTP, resulting in an increase Ras in the active GTP-bound form. The Raf-mediated MAPK pathway is one of several important downstream cascades of Ras. Activated Ras leads to the activation of Raf (ARAF, BRAF, and/or CRAF) the first MAPK kinase of the pathway. Raf phosphorylates and activates MEK1 and/or MEK2 (MAPK kinase), which in turn phosphorylates and activates ERK1 and/or ERK2. ERK1/2 are the ultimate effectors and exert their function on a large number of downstream molecules, both nuclear and cytosolic. ERK1/2 substrates include nuclear components, transcription factors, membrane proteins, and protein kinases that in turn control vital cellular functions including cell cycle progression, differentiation and the control of cellular growth [2].

Section snippets

Noonan syndrome

Noonan syndrome (NS) is an autosomal dominant disorder that affects approximately 1/1000 to 1/2500 newborns. NS is characterized by distinctive craniofacial features, short stature, congenital cardiac anomalies, bleeding disorders and a variable degree neurocognitive delay (for review see [3]). Individuals with NS have an increased risk of cancer. At present four genes, PTPN11 [4], KRAS [5], SOS1 [6•, 7•] and RAF1 [8•, 9•] harboring heterozygous germline mutations cause NS with all genes

LEOPARD syndrome

LEOPARD syndrome (LS) is a rare autosomal dominant disorder with a similar phenotype to NS, including a ‘Noonan-like’ appearance as well as multiple Lentigines, EKG abnormalities, Ocular hypertelorism, Pulmonary valve stenosis, Abnormal genitalia, Retardation of growth, and Deafness (acronym LEOPARD). LS and NS are allelic disorders, caused by different heterozygous missense mutations in the same genes, PTPN11 [15•, 16•] and RAF1 [8] (Table 1). The most common LS associated PTPN11 mutations

Hereditary gingival fibromatosis

Hereditary gingival fibromatosis (HGF) is characterized by a slowly progressive, benign, fibrous overgrowth of the keratinized gingiva [19]. HGF is a genetically heterogenous condition with both autosomal dominant and recessive inheritance reported. One rare autosomal dominant form, HGF Type 1, is caused by an insertion mutation in the SOS1 gene [20] (Table 1). The SOS1 insertion mutation causes a frame-shift that generates 22 novel amino acids before a premature stop codon which abolishes

Neurofibromatosis type 1

Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited disorder affecting approximately 1 in 3000 newborns (for review see [22]). The clinical diagnosis of NF1 is based on the presence of café-au-lait maculae, intertriginous freckling, neurofibromas and plexiform neurofibromas, iris Lisch nodules, osseous dysplasia, optic pathway glioma and/or a first-degree relative with the clinical diagnosis of NF1. In addition, individuals may have a Noonan-like facies, mild neurocognitive

Capillary malformation–arteriovenous malformation

Capillary malformation–arteriovenous malformation syndrome (CM–AVM) is an autosomal dominant inherited disorder characterized by mutifocal capillary malformations which may be associated with arteriovenous malformations and fistulas (for review see [26]). CM–AVM syndrome is caused by heterozygous inactivating mutations in the gene RASA1, which like NF1, encodes a RasGAP [27] (Table 1). The hallmark of this syndrome is the mutifocality of the malformations. AVMs can occur in many tissues

Costello syndrome

Costello syndrome (CS) is a rare developmental disorder with multiple anomalies, including characteristic dysmorphic craniofacial features, failure to thrive, cardiac, musculoskeletal and ectodermal abnormalities and neurocognitive delay (for review see [29]). Individuals with CS are at increased risk of developing neoplasms, both benign and malignant.

Heterozygous germline mutations in HRAS cause CS [30] (Table 1). The distribution frequency of mutations reveals that more than 80% of

Autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by defective lymphocyte apoptosis, an accumulation of nonmalignant lymphocytes and an increase in the risk of developing hematological malignancies [36]. Most cases of ALPS are associated with impaired extrinsic Fas-receptor mediated apoptosis caused by mutations associated with the CD95 pathway [37]. Recently, a cause of ALPS independent of the CD95 pathway has been identified as being due to a germline mutation in NRAS [38] (

Cardio-facio-cutaneous syndrome

Cardio-facio-cutaneous syndrome (CFC), like CS, is rare, and shares many overlapping phenotypic features with NS and CS, and to some extent with NF1. CFC individuals have a Noonan-like facies, cardiac malformations, ectodermal, gastrointestinal, ocular and musculoskeletal abnormalities, with most having short stature (for review see [39]). Neurologic abnormalities are universally present to varying degrees and include hypotonia, motor delay, speech delay and/or learning disability [40]. Four

Legius syndrome (neurofibromatosis 1-like)

Legius syndrome is an autosomal dominant disorder that shares many phenotypic features with NF1. Individuals may have café-au-lait maculae, axillary freckling, mild neurocognitive impairment and macrocephaly with some having a Noonan-like facies. However, the phenotypic features common in NF1 such as neurofibromas, iris Lisch nodules and central nervous system tumors are lacking. Legius syndrome is caused by heterozygous mutations in SPRED1 [46] (Table 1). SPRED1, encodes SPRED1 which is a

Conclusion

The RASopathies, caused by germline mutations in genes encoding components of the Ras/MAPK pathway, underscore the essential role the pathway plays in normal embryonic and postnatal development. In Xenopus, elevated MAPK activity initiates oocyte meiotic maturation, metaphase arrest in cleaving embryos and is essential for mesoderm induction and patterning [48, 49]. Highly controlled MAPK pathway regulation is also observed during Drosophila and Zebrafish embryonic development [50, 51]. In

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

The authors thank patients and families for their ongoing support of research in genetic medicine. The authors apologize for not citing all relevant references due to space limitations. This work was supported in part by NIH grant HD048502 (KAR).

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