Homozygosity for extremely rare mutations in a human gene called SCN9A cause complete insensitivity to pain (congenital pain insensitivity or CPA) and a total lack of the sense of smell (anosmia). The SCN9A gene encodes a sodium channel protein required for transmission of electrical signals from particular nerves in the body to the brain. The failure to feel pain is a dangerous condition as people cannot sense injuries.
The SCN9A gene has 26 exons and encodes a 1977-amino acid polypeptide. Consanguineous matings in three different families have resulted in individuals with CPA/anosmia. In Family 1, a G-to-A transition in exon 15 results in a truncated protein that is 898 amino acids long; in Family 2, deletion of a single base results in a 766-amino acid polypeptide; and in Family 3, a C-to-G transversion in exon 10 yields a 458-amino acid protein.
a. Hypothesize as to how each of the three SCN9A mutations affects gene structure: Why are truncated proteins made in each case?
b. How would you classify the mutant alleles? Do these cause loss of function or gain of function? Are they amorphs, hypomorphs, hypermorphs, neomorphs, or antimorphs?
c. Explain in molecular terms why CPA/anosmia is a recessive condition.
Homozygosity for extremely rare mutations in a human gene called SCN9A cause complete insensitivity to pain (congenital pain insensitivity or CPA) and a total lack of the sense of smell (anosmia). The SCN9A gene encodes a sodium channel protein required for transmission of electrical signals from particular nerves in the body to the brain. The failure to feel pain is a dangerous condition as people cannot sense injuries.
The SCN9A gene has 26 exons and encodes a 1977-amino acid polypeptide. Consanguineous matings in three different families have resulted in individuals with CPA/anosmia. In Family 1, a G-to-A transition in exon 15 results in a truncated protein that is 898 amino acids long; in Family 2, deletion of a single base results in a 766-amino acid polypeptide; and in Family 3, a C-to-G transversion in exon 10 yields a 458-amino acid protein.
a. Hypothesize as to how each of the three SCN9A mutations affects gene structure: Why are truncated proteins made in each case?
b. How would you classify the mutant alleles? Do these cause loss of function or gain of function? Are they amorphs, hypomorphs, hypermorphs, neomorphs, or antimorphs?
c. Explain in molecular terms why CPA/anosmia is a recessive condition.
