Chapter 24, Problem 20CONQ

Familial fatal insomnia (described in Table $\text{24}\text{.6}$) is a prion disease inherited as an autosomal dominant trait. Researchers have identified the PrP gene, located on the short arm of chromosome $\text{20}$, and tried to understand the relationship between the PrP gene sequence and the molecular basis of familial fatal insomnia.

A. It has been found that a rare mutation of codon $\text{178}$, changing an aspartic acid to can asparagine, can cause this disease. In addition, codon $\text{129}$ seems to play a role. The human population is polymorphic at codon $\text{129}$, which may encode valine or methionine. If codon $\text{178}$ is the normal aspartic acid (Asp) codon, it does not seem to matter if valine or methionine is found at position $\text{129}$. In other words, if codon $\text{178}$ is aspartic acid, Met- $\text{129}$ and Val- $\text{129}$ codons are not associated with disease symptoms. However, if codon $\text{178}$ specifies asparagine (Asn), then it does not matter. Familial fatal insomnia seems to require an asparagine at codon $\text{178}$ and a methionine at codon $\text{129}$ in the PrP gene sequence. Suggest a possible reason why this is the case.

B. Also, researchers have compared the sequence of the PrP gene in many people with familial fatal insomnia. Keep in mind that this is a dominant autosomal trait, so people with this disorder have one mutant copy of the PrP gene and one normal copy. People with familial fatal insomnia must have one abnormal copy of the gene that contains Asn- $\text{178}$ and Met- $\text{129}$. The second copy of the gene has Asn- $\text{178}$, and may have Met- $\text{129}$ or Val- $\text{129}$. Some results suggest that people having a Met- $\text{129}$ codon in this second copy of the PrP gene causes the disease to develop more rapidly than in people who have Val- $\text{129}$ in the second copy. Propose an explanation why disease symptoms may occur more rapidly when Met- $\text{129}$ is found in the second copy of the PrP gene.