WBR0121

Author	[[PageAuthor::William J Gibson (reviewed by Rim Halaby, M.D. [1])]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Genetics
Sub Category	SubCategory::Reproductive, SubCategory::General Principles
Prompt	[[Prompt::A 48 year old woman presents to her primary care physician complaining of abdominal pain, bloating and early satiety. She describes these symptoms as increasing in severity over the past several weeks. The physician notes mild pain with palpation on abdominal exam. The patient is referred to OB/GYN where a pelvic exam is performed. Pelvic exam reveals a large mass of the left ovary. Laboratory studies are significant for increased CA-125. CT reveals a large mass of the left ovary which has extended to but not invaded the omentum. The patient udergoes total abdominal historectomy. Upon surgical removal, the tumor is analyzed by the pathologist who diagnoses high-grade serous ovarian adenocarcinoma. Molecular analysis demonstrates the following sequencing results of the TP53 gene: Which of the following is the most appropriate term for the molecular effect of this mutation?]]
Answer A	AnswerA::Loss of heterozygosity
Answer A Explanation	AnswerAExp::While loss of heterozygosity is a term commonly used with tumor suppressors, we see here that the mutation is heterozygous.
Answer B	AnswerB::Dominant negative
Answer B Explanation	AnswerBExp::A dominant negative mutation refers to a mutation whose gene product disrupts the function of the normal, wild-type gene product.
Answer C	AnswerC::Epistasis
Answer C Explanation	AnswerCExp::Epistasis is a phenomenon in which the expression of one gene depends on the presence of one or more "modifier genes"
Answer D	AnswerD::Haploinsufficiency
Answer D Explanation	AnswerDExp::While mutation of one allele causes disease, the molecular mechanism of this mutation is not simply decreased function of the monomeric gene product. In this case, the mutant protein interferes with the function of the wild-type.
Answer E	AnswerE::Loss of function
Answer E Explanation	AnswerEExp::While this mutation may cause the protein to lose some of its biological function, it does so in a dominant negative manner. Loss of function mutations typically act in a recessive manner at the molecular level.
Right Answer	RightAnswer::B
Explanation	[[Explanation::The mutation in this image is a heterozygous mutation, meaning that one copy of the TP53 gene is mutated and the other is not. TP53 is an important tumor suppressor. A heterozygous mutation which leads to a phenotype (in this case cancer) is an example of a dominant negative mutation. On the molecular level, the p53 protein forms a homotetramer. When one allele of the TP53 gene is mutated and a mutant protein joins the tetramer, then the function of the tetramer is lost. Thus, one mutated allele causes the p53 protein to lose 15/16 of its biological function. On the other hand, a deletion of p53 would cause a 50% decrease in its biological function. For this reason, p53 is mutated and not deleted. Educational Objective: A dominant negative mutation refers to a mutation whose gene product disrupts the function of the normal, wild-type gene product. References: First Aid 2014 page 76; First Aid 2012 page 87, 253]]
Approved	Approved::Yes
Keyword	WBRKeyword::TP53, WBRKeyword::P 53, WBRKeyword::p53, WBRKeyword::Mutation, WBRKeyword::Genetics
Linked Question	Linked::
Order in Linked Questions	LinkedOrder::