-year-old girl, T.N., has been noted to have increasing difficulty standing up after sitting on the floor. Her serum level of creatine kinase is grossly elevated. Although a female, the presumptive clinical diagnosis is Duchenne muscular dystrophy. Females with DMD are rare. Identify three mechanisms of mutation that could account for the occurrence of DMD in a female.

8. In patients with osteogenesis imperfecta, explain why the missense mutations at glycine positions in the triple helix of type I collagen are confined to a limited number of other amino acid residues (Ala, Ser, Cys, Arg, Val, Asp).

9. Glucose-6-phosphate dehydrogenase (G6PD) is encoded by an X-linked gene. G6PD loss-of-function mutations can lead to hemolysis on exposure to some drugs, fava beans, and other compounds (see Chapter 18). Electrophoresis of red blood cell hemolysates shows that some females have two G6PD bands, but males have a single band. Explain this observation and the possible pathological and genetic significance of the finding of two bands in an African American female.

10. A 2-year-old infant, the child of first-cousin parents, has unexplained developmental delay. A survey of various biochemical parameters indicates that he has a deficiency of four lysosomal enzymes. Explain how a single autosomal recessive mutation might cause the loss of function of four enzyme activities. Why is it most likely that the child has an autosomal recessive condition, if he has a genetic condition at all?

11. The effect of a dominant negative allele illustrates one general mechanism by which mutations in a protein cause dominantly inherited disease. What other mechanism is commonly associated with dominance in genes encoding the subunits of multimeric proteins?

12. The clinical effects of mutations in a housekeeping protein are frequently limited to one or a few tissues, often tissues in which the protein is abundant and serves a specialty function. Identify and discuss examples that illustrate this generalization, and explain why they fit it.

13. The relationship between the site at which a protein is expressed and the site of pathological change in a genetic disease may be unpredictable. In addition, the tissue that lacks the mutant protein may even be left unaffected by disease. Give examples of this latter phenomenon and discuss them.

14. The two pseudodeficiency alleles of hex A are Arg247Trp and Arg249Trp. What is the probable reason that the missense substitutions of these alleles are so close together in the protein?

15. Why are gain-of-function mutations in proteins, as seen with the autosomal dominant PCSK9 mutations that cause hypercholesterolemia, almost always missense mutations?

16. What are the possible explanations for the presence of three predominant alleles for Tay-Sachs disease in Ashkenazi Jews? Does the presence of three alleles, and the relatively high frequency of Tay-Sachs disease in this population, necessarily accord with a heterozygote advantage hypothesis or a founder effect hypothesis?

17. All of the known loci associated with Alzheimer disease do not account for the implied genetic risk. Identify at least three other sources of genetic variation that may account for the genetic contribution to AD.

18. Propose a molecular therapy that might counteract the effect of the CUG expansions in the RNAs of myotonic dystrophy 1 and 2 and that would reduce the binding of RNA-binding proteins to the CUG repeats. Anticipate some possible undesirable effects of your proposed therapy.

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