Inheritance and Mutations in a Single-Gene Disorder
This activity builds on information presented in the short film Genes as Medicine. Students interpret actual pedigrees to determine the inheritance pattern of Leber congenital amaurosis (LCA), an inherited form of blindness. They also examine protein sequence data to explore mutations that can cause LCA.
LCA is a disease that primarily affects the retina. Scientists have identified several types of LCA with different genetic causes and patterns of vision loss. In this three-part activity, students examine a form of LCA caused by mutations in the gene RPE65.
The activity reinforces the connection between genotype and phenotype and illustrates that genes can have multiple alleles, including multiple disease-causing alleles. In the first part of the activity, students analyze several pedigrees of families with members who have LCA. The pedigrees were obtained from a published scientific study. In the second part, students explore mutations in the RPE65 protein in individuals with LCA and discover that some individuals (known as compound heterozygotes) carry two different disease-causing alleles. In the last part of the activity, students reflect on how LCA can be treated using gene therapy.
Student Learning Targets
- Describe the relationship between genotype and phenotype.
- Use a pedigree to infer genotypes and determine the most likely inheritance pattern of a single-gene trait.
- Analyze amino acid sequence data to identify mutations.
allele, compound heterozygote, gene sequencing, gene therapy, genotype, Leber congenital amaurosis (LCA), pedigree chart, phenotype
Morimura, Hiroyuki, Gerald A. Fishman, Sandeep A. Grover, Anne B. Fulton, Eliot L. Berson, and Thaddeus P. Dryja. “Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or Leber congenital amaurosis.” Proceedings of the National Academy of Sciences 95, 6 (1998): 3088–3093. https://doi.org/10.1073/pnas.95.6.3088.
Li, Yumei, Hui Wang, Jianlan Peng, Richard A. Gibbs, Richard Alan Lewis, James R. Lupski, Graeme Mardon, and Rui Chen. “Mutation survey of known LCA genes and loci in the Saudi Arabian population.” Investigative Ophthalmology and Visual Science 50, 3 (2008): 1336–1343. https://doi.org/10.1167/iovs.08-2589.
Russell, Stephen, Jean Bennett, Jennifer A. Wellman, Daniel C. Chung, Zi-Fan Yu, Amy Tillman, Janet Wittes, et al. “Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: A randomised, controlled, open-label, phase 3 trial.” The Lancet 390, 10097 (2017): 849–860. https://doi.org/10.1016/s0140-6736(17)31868-8.
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HS-LS1-1, HS-LS3-1; SEP2, SEP6
3.A.1, 3.A.3, 3.C.1; SP1, SP6
3.1, 3.4, B.4
Math.S-IC.2; MP2, MP4