Chapter 19, Problem 19P

Neurofibromatosis type 1 (NF1; also known as von Recklinghausen disease) is an inherited dominant disorder. The phenotype (see Fig. 11.19) usually involves the production of many skin neurofibromas (benign tumors of the fibrous cells that cover the nerves).

a.	Is it likely that NF1 is a tumor-suppressor gene or an oncogene?
b.	Are the NF1 neurofibromatosis-causing mutations that are inherited by affected children from affected parents likely to be loss-of-function or gain-of-function mutations?
c.	Neurofibromin, the protein product of NF1, has been found to be associated with the Ras protein. Ras is involved in the transduction of extracellular signals from growth factors. The active form of Ras (the form initiating the signal transduction cascade causing proliferation) is complexed with GTP; the inactive form of Ras is complexed with GDP. Would the wild-type neurofibromin protein favor the formation of Ras–GTP or Ras–GDP?
d.	Which of the following events in a normal cell from an individual inheriting a neurofibromatosis-causing allele could cause the descendants of that cell to grow into a neurofibroma? i. A second point mutation in the allele of NF1 inherited from the affected parent ii. A point mutation in the allele of NF1 inherited from the normal parent iii. A large deletion that removes the NF1 gene from the chromosome inherited from the affected parent iv. A large deletion that removes the NF1 gene from the chromosome inherited from the normal parent v. Mitotic chromosomal nondisjunction or chromosome loss vi. Mitotic recombination in the region between the NF1 gene and the centromere of the chromosome carrying NF1 vii. Mitotic recombination in the region between the NF1 gene and the telomere of the chromosome carrying NF1
e.	A much rarer form of neurofibromatosis exists called segmental neurofibromatosis. In this form of the disease, neither parent of the patient has any clinical sign of the disease. The tumors in the patient are restricted to one part of the body, like the right leg. Suggest an explanation for the genesis of segmental neurofibromatosis that clarifies why it is restricted to one part of the body.