Hey Georgian Life readers! As you know, genes are encoded by the DNA contained in every cell in your body and control all cellular functions including growth, division, and longevity. Acquisition of mutations in cancer sensitive “hotspots” is a leading cause of cancer. These somatic (acquired) mutations occur during our lifetime from damaged DNA arising from tobacco use, exposure to ultraviolet radiation, and age.

Similar to somatic mutations, germline (hereditary) mutations in cancer susceptibility genes in some cases do lead to cancer, such as mutations in BRCA1/2. However, unlike a somatic mutation, a germline mutation is present in every cell from fertilization to embryogenesis to birth and therefore these mutations can have dire effects on development which lead to congenital disorders. Germline mutations in genes encoding proteins that function in the RAS-mitogen-activated protein kinase (MAPK- pronounced “map kay”) pathway, a pathway dysregulated in cancer, causes disorders referred to as “RASopathies” which include Noonan and Noonan-like syndromes.

Noonan syndrome (NS) is an autosomal dominant disorder first described by Jacqueline Noonan, a paediatric cardiologist, in 1962. The clinical features associated with NS include short stature, facial dysmorphism and congenital heart defects. The characteristic facial phenotypes include wideset eyes (hypertelorism), broad forehead, wide nasal base, and low-set posteriorly rotated ears. Many of the patients have developmental delay and intellectual disability. Heart defects are seen in 80% of patients associated primarily with pulmonary valve stenosis but hypertrophic cardiomyopathy, a thickening of cardiac tissue which leads to heart dysfunction is also common. The phenotypic features of Noonan-like syndromes Costello, cardio-facio-cutaneous (CFC), Legius, neurofibromatosis type 1 (NF1), and NS with multiple lentigines (NSML, formerly called LEOPARD) share significant clinical overlap with NS including the distinct facial features, developmental delay, and cardiac defects.

The RASopathies are disorders associated with gain- or loss-of function mutation in genes encoding proteins in the RAS-MAPK pathway. The RAS-MAPK pathway is an essential signaling cascade critical to cellular function and normal development. In humans, there are multiple RAS genes including H-RAS, K-RAS, and N-RAS family members. RAS proteins are coupled to cell surface receptor activity. Receptor activation by growth factors activates RAS followed by the sequential activation of RAF-MEK-ERK leading to activation of transcription factors which turn on/off genes that control cell proliferation, survival, and differentiation. The RAS-MAPK cascade is tightly regulated at every step. Abnormal activation of the RAS-MAPK pathway is commonly observed in cancer.

In 1994, genetic analysis of a large family with NS definitively established the first NS locus. In 2001, it was determined that mutations in PTPN11 (encodes a protein called SHP-2) contained in the NS locus caused NS. SHP-2 is a protein that regulates cell signaling through the MAPK pathway. Gain-of-function mutations in PTPN11 have been identified in approximately 50% of NS patients and are found in acute myeloid leukemia. Germline mutations in K-RAS and N-RAS, as well as SOS1 (an activator of RAS), and RAF1 (one of the signaling proteins in the MAPK cascade) have also been identified to cause NS. Germline mutations in H-RAS have been identified in patients with Costello syndrome and mutations in K-RAS, BRAF (a family member of RAF1), and MAP2K1/2 (the genes which encode MEK1 and MEK2) have been identified in patients with CFC syndrome. NF1 syndrome has been found to be caused by loss-of-function mutation in the NF1 gene which is a negative regulator of RAS. These NS mutants are believed to cause the syndromes primarily, if not exclusively, by potentiating signaling through the RAS-MAPK pathway.

Although individually these syndromes are rare, collectively the RASopathies are among the most common genetic conditions in humans. For more information visit the RASopathies Network online. Their mission is to advance research of the RASopathies by bringing together families, clinicians and scientists.

Photo credit: Rick Guidotti, Positive Exposure in collaboration with RASopathies Network.

Submitted by: Dr. Oliver Kent, Scientific Associate and cancer researcher at the Princess Margaret Cancer Centre.

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