This week, we are sharing another USMLE® Step 1-style practice question to test your knowledge of medical topics. Today’s case focuses on a 6-month-old boy which is brought to the clinic for a well-child visit. His mother expresses concern that there is inward deviation of his left eye. The patient most likely has a mutation in a gene that normally does which of the following functions? Can you figure it out?
A 6-month-old infant boy is brought to the clinic for a well-child visit. His mother expresses concern that there is inward deviation of his left eye. His older sibling was recently diagnosed with osteosarcoma. Examination looking for the red reflex is shown in the image below. The patient most likely has a mutation in a gene that normally does which of the following functions?
Image reproduced from: Wikimedia Commons
A. Binding to DNA to increase transcription of p21
B. Inhibition of cyclin E cyclin-dependant kinase 2
C. Conversion of GTP to GDP and phosphate
D. Inactivation of E2F
E. Increases expression of cyclins and cyclin-dependant kinases
Scroll down for the correct answer!
The correct answer to today’s USMLE® Step 1 Question is…
D. Inactivation of E2F
Before we get to the Main Explanation, let’s look at the incorrect answer explanations. Skip to the bottom if you want to see the correct answer right away!
Incorrect answer explanations
A. Binding to DNA to increase transcription of p21
Incorrect: This action is performed by p53, which is a tumor suppressor not involved in retinoblastoma. P53 mutations are involved in most human cancers. A hereditary mutation of p53 occurs in Li-Fraumeni syndrome, which is autosomal dominant.
B. Inhibition of cyclin E cyclin-dependant kinase 2
Incorrect: This action is performed by p21. The transcription of p21 is increased by the p53.
C. Conversion of GTP to GDP and phosphate
Incorrect: This function is performed by KRAS, which is a proto-oncogene. Mutation of KRAS to an oncogene is involved in colon cancer, lung cancer, and pancreatic cancer.
E. Increases expression of cyclins and cyclin-dependant kinases
Incorrect: c-MYC is a transcription factor that increases the expression of cyclins and cyclin-dependant kinases. This is a proto-oncogene that gets mutated to an oncogene in Burkitt lymphoma.
Main Explanation
This infant has retinoblastoma, which typically presents as leukocoria (whitening of the red reflex) in a young child under the age of two years. Another common feature that is seen in this case is strabismus, which is a misalignment of the eyes. Retinoblastoma can arise from heritable and non-heritable mutations of retinoblastoma gene (RB gene). The family history of osteosarcoma in his older sibling suggests this is a familial retinoblastoma.
Rb is a tumor suppressor gene that normally functions to inactivate E2F, which prevents the cell from progressing from the G1 → S phase. To remove RB from E2F, RB must be phosphorylated, which is normally done after the cell receives a growth signal. However, if DNA is damaged, RB remains attached to the E2F, which prevents cells with damaged DNA from undergoing further growth and division.
RB1 gene mutation is a loss-of-function mutation of the tumor suppressor gene and requires both alleles of the gene to be mutated before cancer develops (2-hit hypothesis). Patients with RB1 gene mutation can develop retinoblastoma and osteosarcoma.
Major Takeaway
Rb is a tumor suppressor gene that undergoes mutational inactivation that can lead to retinoblastoma and osteosarcoma. It normally functions to inactivate E2F, which prevents the cell from progressing from the G1 → S phase.
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