Mutant genes that affect several organ systems and bodily functions frequently show variable expressivity, a phenomenon referred to as phenotypic variation. The most striking example of phenotypic variability is manifest in an autosomal-dominant condition characterized by the appearance of café au lait spots on the skin and cutaneous and subcutaneous neurofibromas. These symptoms are associated with which of the following?
(A) familial adenomatous polyposis (B) FH
© Li Fraumeni syndrome
(D) von Hippel-Lindau syndrome
(E) von Recklinghausen disease (type I neurofibromatosis)
Explanation
(E) von Recklinghausen disease (neurofibromatosis, type I), an autosomal-dominant disorder, is one of the most striking disorders that exhibits variable expressivity (phenotypic variation). Symptoms can range from the benign appearance of café au lait spots to severe disfiguring cutaneous neurofibromas, sarcomas, and gliomas. This disorder is caused by disruption in the neurofibromin gene whose protein product functions the catalysis of inactivation of the signaling protein RAS. FAP coli (choice A) is a disorder that results in the generation of numerous small polyps in the colon by the time an individual reaches age 20. Although the polyps are asymptomatic, they are a significant contributory factor to risk and likelihood of colon cancer. This disorder is caused by mutations in the APC gene, is inherited in autosomal-dominant fashion, and its penetrance is 100% in all afflicted individuals. FH (choice B) is caused by mutations in the gene for the LDLreceptor. Inheritance is autosomal dominant with 100% penetrance. FH sufferers may be either heterozygous or homologous for a particular mutation in the receptor gene. Homozygotes exhibit grossly elevated serum cholesterol (primarily in LDLs). The elevated levels of LDLs result in their phagocytosis by macrophages. These lipidladen phagocytic cells tend to deposit within the skin and tendons, leading to xanthomas. A greater complication results from cholesterol deposition within the arteries, leading to
atherosclerosis, the major contributing factor of nearly all cardiovascular diseases. LFS (choice C) is a rare form of autosomal-dominant inherited cancer caused by mutations in the tumor suppressor gene, p53. The disruption in the function of p53 leads to aberrant cell-cycle regulation and development of sarcomas, brain tumors, breast cancer, and leukemias. Cancer occurs in 50% of afflicted individuals by the time they are 30 years of age. VHL syndrome (choice D) is an inherited form of renal carcinoma that is caused by mutations in a tumor suppressor gene identified as the VHLgene.