Problem 1

1. Problem 1 • James is the only person in his kindred affected by DMD. He has one unaffected brother, Joe. DNA analysis show that James has a deletion in the DMD gene and that Joe has received the same maternal X chromosome but without a deletion. What genetic counseling would you give the parents regarding the recurrence risk of DMD in future pregnancy problem 4 Chapter 12 text

2. Answer Problem 1 Note DMD X-lined • James may have a new mutation on the X chromosome because Joe inherited the same X chromosome from his mother, and in neither the mother nor Joe was the deletion present. If this is the case, there is no risk of recurrence. Alternatively, the mother may be a mosaic, and the mosaicism includes her germline. In this case, there is a definite risk that the mutant X could be inherited by another son or passed to a carrier daughter. About 5 to 15 present of cases of this type appear to be due to maternal germline mosaicism. Thus, the risk is half of this figure for her male offspring, because the chance that a son will inherit the mutant X is 1/2x0.05 to 0.15 =2.5 to 7.5 percent. If new mutation no risk ? Joe James New mutation 10-4 same chromosome no mutation If mother has germline mosaicism then 1/2x 0.05 to 0.15=2.5% to 7.5%

3. Chromosome 12 Beef promoter Exon 2 Exon 3 Exon 4 Exon 5 Exon 1 Chromosome 9 Up promoter Exon 2 Exon 3 Exon 4 Exon 5 Exon 1 Exons of up gene exon 5 contains domain 1 and exon 2 contains domain 2 Draw Problem 2 The beef gene is a located on chromosome 12. It is expressed in all tissues at high levels. The up gene is located on chromosome 9 it is expressed only in liver cells in a cell cycle dependent fashion. The up gene contains two domains. Domain 1 contains a kinase which is important for cell proliferation. Domain 2 inhibits the kinase activity of domain 1 when it is phosphorylated. The beef gene contains 3 domains all of which are a mystery. You receive some liver tumor cells. Cytogenetic analysis indicates a chromosome translocation between chromosome 12 and 9. You also notice that the cell have high levels of up kinase activity. From the diagram below draw one possible construct that may explain the presence of the tumor and the increase kinase activity of up. From your hypothesis explain why up the cells are rampantly proliferating.

4. Answer problem 2 From the diagram below draw one possible construct that may explain the presence of the tumor and the increase kinase activity of up. Chromosome 12 Beef promoter Exon 2 Exon 3 Exon 4 Exon 5 Exon 1 Chromosome translocation Chromosome 9 Up promoter Exon 2 Exon 3 Exon 4 Exon 5 Exon 1 Exons of up gene exon 5 contains domain 1 and exon 2 contains domain 2 Draw Chromosome 9 Chromosome 12 Up promoter Exon 2 Exon 3 Exon 4 Exon 5 Exon 1 Before the translocation the up gene was expressed in a cell cycle and tissue specific dependent fashion. It also contained a domain which modulated its kinase activity. The new up gene (a beef hybrid containing the up kinase domain) is now expressed at high levels in all tissues and does not contain a domain 1 which functioned to regulate the protein. This protein might stimulate cell proliferation in a cell cycle independent fashion resulting in a tumor.

5. Problem 3 • A patient with retinoblastoma has a single tumor in one eye; the other eye is free of tumors. • A. What steps would you take to try to determine whether this was sporadic or heritable retinoblastoma? • B. What genetic counseling would you provide? • C. What information should the parents have before a subsequent pregnancy? Text chapter 16 problem 1

6. Answer Problem 3 • A. What steps would you take to try to determine whether this was sporadic or heritable retinoblastoma? • Family history, careful examination of both parents retinas, cytogenetic analysis if the tumor is associated with other malformations, mutation identification. • B. What genetic counseling would you provide? • Advise parents of the risk, but point out that a future child could be examined immediately after birth and at short intervals for some time to make sure that if tumors develop, they are detected and treated early. • C. What information should the parents have before a subsequent pregnancy? • The parents should be informed of the risk of disease in subsequent pregnancies, the availability of prenatal diagnosis, and the impact of the disease should it recur.

7. Problem 4 • Suppose that you had the ability to introduce normal copies of a gene into a tumor cell that had mutations in the gene that caused it to promote tumor growth • a. If the mutations were in a tumor suppressor gene, would you expect that these normal transgenes would block the tumor-producing activity of the mutations? Why or Why not? • b. If the mutations were of the oncogene type, would you expect that the normal transgenes would block their tumor-promoting activity? Why or why not?

8. Answer Problem 4 • a. If the mutations were in a tumor suppressor gene, would you expect that these normal transgenes would block the tumor-producing activity of the mutations? Why or Why not? • Mutations in a tumor suppressor gene are recessive and due to loss of function. That function can be restored by the introduction of a wild-type allele. • b. If the mutations were of the oncogene type, would you expect that the normal transgenes would block their tumor-promoting activity? Why or why not? • Mutations in an oncogene are dominant and due to gain of function (over expression or misexpression). The normal function will not inhibit these mutants, and the introduced gene would be ineffective in restoring the normal phenotype