A 4-year-old girl is brought to the clinic due to an inward deviated right eye. Examination shows a pale red reflex in the right eye relative to the left eye. Dilated funduscopic examination reveals a well-circumscribed white mass within the retina. Genetic analysis shows a germline mutation in the patient's cells leading to development of the mass. Which of the following is the most likely function of the protein affected by this patient's gene mutation?

Question

A 4-year-old girl is brought to the clinic due to an inward deviated right eye.  Examination shows a pale red reflex in the right eye relative to the left eye.  Dilated funduscopic examination reveals a well-circumscribed white mass within the retina.  Genetic analysis shows a germline mutation in the patient's cells leading to development of the mass.  Which of the following is the most likely function of the protein affected by this patient's gene mutation?

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11ec160b_39fb_8948_9249_4b545a96796f_MD0001_00 This patient's pale red reflex and well-circumscribed white mass within the retina are indicative of retinoblastoma. Retinoblastoma is an intraocular tumor caused by inactivating mutations affecting the RB1tumor suppressor gene with subsequent dysregulation of the cell cycle. The cell cycle consists of the following stages: Gap phase 0 (G0 phase) is a resting stage in which the cell cycle is suspended. Interphase is the stage in which the cell prepares for division. Interphase is subdivided into the G1 phase (synthesis of RNA, protein, lipid, and carbohydrate), S phase (DNA replication), and the G2 phase (ATP synthesis). Mitosis (M) is the stage in which the cell divides into two daughter cells. Checkpoints occur at the G1/S and G2/M transitions, allowing the cell cycle to be stopped if damaged DNA is detected by cyclins and cyclin-dependent kinases. DNA repair mechanisms are activated, but if the DNA damage is too substantial, the cell undergoes apoptosis. The RB1 gene encodes the Rb protein that regulates the G1/S checkpoint. In its active form, Rb protein binds and inhibits E2F transcription factors, thereby halting the cell cycle. In contrast, when a cell is ready to divide, Rb protein is phosphorylated by cyclin-dependent kinases, allowing the cell to proceed through the G1/S checkpoint. Loss-of-function mutations affecting the Rb protein result in unrestricted progression through the G1/S checkpoint, leading to uncontrolled cell division. Inciting RB1 mutations have been linked to retinoblastoma and osteosarcoma. (Choice A) Many receptor tyrosine kinases have stimulatory effects on cell growth, and increased receptor activity occurs with a variety of cancers. For example, overexpression of EGFR and MET are associated with non-small cell lung cancer, and HER2 is associated with breast cancer. (Choice B) Abnormal K-Ras GTPase function due to a KRAS mutation prevents the conversion of GTP to GDP, which results in constant activation of the MAPK pathway and uncontrolled cellular proliferation. KRAS mutations are associated with lung and colorectal cancers, not retinoblastoma. (Choice C) Tumor suppressor protein p53 arrests the cell cycle at the G1/S checkpoint if DNA damage is detected and initiates cell apoptosis if DNA repair fails. Mutations of p53 are associated with most cancers, particularly Li-Fraumeni syndrome (sarcoma, breast, leukemia, and adrenal cancers). Rb and p53 proteins are both critical components of tumor suppression pathways, and their normal function complements one another to prevent cancer progression. (Choice E) BRCA1 and BRCA2 are two of many DNA repair genes that have been identified. When mutated, these genes are associated with an increased risk of breast and ovarian cancer. Educational objective: Retinoblastoma is associated with inactivating mutations of the RB1 tumor suppressor gene, which normally restricts cells from passing the G1/S checkpoint until the cell is ready to divide. Impaired function of the Rb protein allows unrestricted progression through the G1/S checkpoint, leading to uncontrolled cell division. __________ References: Molecular mechanisms underlying RB protein function. (http://www.ncbi.nlm.nih.gov/pubmed/23594950) RB and cell cycle progression. (http://www.ncbi.nlm.nih.gov/pubmed/16936740)

A 4-Year-Old Girl Is Brought to the Clinic Due to an Inward