Question

There are at least eight known progressive neuronal dysfunction diseases in humans that are caused by abnormal numbers of CAG repeats within the coding regions of specific genes. Genes carrying such mutations are typically of the gain-offunction class and often share a common mechanism of progressive pathogenesis. Why are such genes "gain-of-function"? Speculate on why such diseases are probably caused by a common mechanism of pathogenesis.

Short answer

Answer: Genes with abnormal numbers of CAG repeats are classified as "gain-of-function" because the mutations result in altered or enhanced activity of the gene product. The elongated polyQ tracts lead to a toxic gain of function, causing the protein to misfold and aggregate, which in turn has detrimental effects on the cell, causing cellular dysfunction and neuronal cell death. The common mechanism of pathogenesis in progressive neuronal dysfunction diseases caused by abnormal CAG repeats is likely related to the toxic gain of function due to elongated polyQ tracts. Since these diseases often have similar symptoms, and involve mutations in different genes with CAG repeats, the toxic effects of abnormally elongated polyQ tracts appear to be a common pathogenic process. This includes intracellular protein aggregation, cellular dysfunction, disruption of protein-protein interactions, and ultimately, neurodegeneration.

Step-by-step solution

Defining gain-of-function genes

Gain-of-function genes are those that have an acquired mutation that results in an altered or enhanced activity of the gene product compared to its wild-type counterpart. This can lead to changes in the cellular function, often causing cell damage or dysregulation.

Understanding CAG repeats

CAG repeats refer to tandem repeats of the trinucleotide sequence CAG (cytosine-adenine-guanine) in a gene's coding region. The abnormal number of CAG repeats can cause genetic mutations, leading to various neurodegenerative diseases in humans such as Huntington's disease, Spinocerebellar ataxia, and others.

Effects of abnormal CAG repeats

The presence of an abnormal number of CAG repeats can lead to the elongation of polyglutamine (polyQ) tracts within the protein encoded by the gene. Extended polyQ tracts often result in misfolded proteins, which can aggregate and form intracellular inclusions. This contributes to cellular dysfunction and ultimately leads to neurodegeneration.

Explaining why these genes are gain-of-function

Genes with abnormal CAG repeats are considered gain-of-function because the mutations result in altered or enhanced activity of the gene product. The elongated polyQ tracts lead to a toxic gain of function, causing the protein to misfold and aggregate. This, in turn, has detrimental effects on the cell, causing cellular dysfunction, and even neuronal cell death.

Discussing the common mechanism of pathogenesis

The common mechanism of pathogenesis in progressive neuronal dysfunction diseases caused by abnormal CAG repeats is likely related to the toxic gain of function due to elongated polyQ tracts. Since these diseases often have similar symptoms, and involve mutations in different genes with CAG repeats, the toxic effects of abnormally elongated polyQ tracts appear to be a common pathogenic process. This might include intracellular protein aggregation, cellular dysfunction, disruption of protein-protein interactions, and ultimately, neurodegeneration.