Question

Recall from the opening example in this chapter that Leber congenital amaurosis (LCA), a form of congenital blindness in humans, can be caused by homozygosity for recessive mutations in the RPE65 gene. Recently, a rare dominant mutation in RPE65 has been implicated as one cause of an eye disease called retinitis pigmentosa, which is characterized by retinal degeneration that can progress to blindness. The dom- inant RPE65 mutation is a missense mutation causing amino acid 447 in the polypeptide to change from Asp to Glu. Little is known about the nature of the mutant protein. a. Do you think that the dominant allele is more likely a loss-of-function or a gain-of-function mutation? Explain.

Answer 1

The dominant mutation in RPE65 linked to retinitis pigmentosa is likely a gain-of-function mutation. This type of mutation can add a new function or an abnormal activity to the protein, unlike recessive mutations, which typically involve loss of function and can lead to diseases like Lowe disease. Dominant disorders, such as Huntington's disease, often involve abnormal proteins that cause disease symptoms with just one mutant allele.

Step-by-step explanation:

The rare dominant mutation in the RPE65 gene causing retinitis pigmentosa is more likely a gain-of-function mutation as opposed to a loss-of-function. Typically, when thinking about dominant versus recessive genetic disorders, if a single functional copy of a gene is sufficient to produce a normal phenotype, then a dominant allele exhibiting symptoms would suggest an altered function, which could be due to a gain of abnormal function or a dominant-negative effect rather than merely losing the gene's function. Gain-of-function mutations can result in a protein with a new or abnormal function, while loss-of-function mutations usually result in reduced or abolished protein function. This new function can interfere with cellular processes or create new abnormal functions that lead to disease, such as in the case of retinitis pigmentosa, where the missense mutation changes aspartate (Asp) to glutamate (Glu) at the 447th position in the RPE65 protein.

Diseases caused by recessive alleles, such as Lowe disease or sickle cell anemia, usually result from a lack of a gene's product or the production of a non-functional version of a protein. For example, Lowe disease is a result of a mutation that prevents the synthesis of a critical enzyme in the Golgi apparatus, leading to the disease symptoms. Conversely, autosomal dominant disorders like Huntington's disease present symptoms with only one copy of the mutant allele, often due to the production of a toxic or abnormal protein that in turn affects the nervous system and leads to the symptoms observed.