You are a scientist studying two related congenital diseases, Noonan syndrome and Tiger syndrome. People with these syndromes are characterized by differences in heart development and skeletal morphology. Individuals with either syndrome are also susceptible to certain types of cancer, such as leukemia. Some cases of Noonan syndrome are caused by dominant activating variants of the MAP kinase-kinase-kinase protein Raf. The genetic basis of Tiger syndrome is unknown. Your team is involved in a clinical trial, which finds that drugs that inhibit Raf are associated with improved outcomes in cancer patients with Noonan syndrome. You find that Tiger syndrome patients also respond to the treatment, so you sequence the Raf gene in several patients, but find no mutations. Based on what you know about the MAP kinase pathway, you sequence the Sos gene in Tiger syndrome patients. You find that 5 out of 10 patients in your trial have a SNP that changes the amino acid Thr266 to Lys (T266K). Introducing this variant of Sos into cells in culture leads to increased levels of phosphorylated ERK compared to controls. Q1: The mutations that cause Noonan and Tiger syndrome are dominant. How does the Sos activity change because of the T266K substitution? How does this explain its dominance? Q2: Phosphorylated ERK is an activated kinase, some of which enters the nucleus. ERK has multiple possible substrates in the nucleus, including transcription factors. Describe how ERK activity communicates to the genome to begin expressing a specific gene(s).
You are a scientist studying two related congenital diseases, Noonan syndrome and Tiger syndrome. People with these syndromes are characterized by differences in heart development and skeletal morphology. Individuals with either syndrome are also susceptible to certain types of cancer, such as leukemia. Some cases of Noonan syndrome are caused by dominant activating variants of the MAP kinase-kinase-kinase protein Raf. The genetic basis of Tiger syndrome is unknown.
Your team is involved in a clinical trial, which finds that drugs that inhibit Raf are associated with improved outcomes in cancer patients with Noonan syndrome. You find that Tiger syndrome patients also respond to the treatment, so you sequence the Raf gene in several patients, but find no mutations.
Based on what you know about the MAP kinase pathway, you sequence the Sos gene in Tiger syndrome patients. You find that 5 out of 10 patients in your trial have a SNP that changes the amino acid Thr266 to Lys (T266K). Introducing this variant of Sos into cells in culture leads to increased levels of phosphorylated ERK compared to controls.
Q1: The mutations that cause Noonan and Tiger syndrome are dominant. How does the Sos activity change because of the T266K substitution? How does this explain its dominance?
Q2: Phosphorylated ERK is an activated kinase, some of which enters the nucleus. ERK has multiple possible substrates in the nucleus, including transcription factors. Describe how ERK activity communicates to the genome to begin expressing a specific gene(s).
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