An 8-year-old boy has failure to thrive, alopecia totalis, localized scleroderma, a small face and jaw, a “beak” nose, wrinkled skin, and stiff joints. He is determined to have a single-point mutation in a nuclear protein, which is a silent mutation in terms of the primary structure of the protein. How could such a mutation lead to a disease?
Correct Answer: By creating an alternative splice site in the gene
Description: The child is expressing the symptoms of Hutchinson-Gilford progeria, a premature aging disease, which is due to a mutation in the LMNA gene, which encodes lamin A, a nuclear protein. The most common mutation is C1824T, in which the normal cytosine at position 1,824 of the gene is replaced by a thymine. This is a silent mutation as far as the protein is concerned-G608G. However, the introduction of the T creates a cryptic splice site in the gene, such that as the hnRNA is processed, a lamin A mRNA is created that is missing 150 nucleotides, corresponding to a loss of 50 amino acids near the carboxy terminal of the protein. Under normal conditions, lamin A is farnesylated, which allows the protein to be attached to the endoplasmic reticulum membrane. During processing, the enzyme AMPSTE24 cleaves part of the carboxy terminal, releasing the farnesylated portion of the protein such that lamin A can be transferred to the nucleus, where it is involved in providing a scaffold for the nuclear membrane. In the mutant protein (progerin), the site of cleavage is lost owing to the loss of the C-terminal amino acids, although the site of farnesylation still remains. Thus, the progerin that reaches the nucleus is still bound to the nuclear membrane, distorting the nuclear membrane and contributing to nuclear instability. Chromatin binding to the nuclear membrane is also altered, as are the phosphorylation sites in progerin, which makes it more difficult for the nuclear membrane to dissolve during mitosis. Because this is a silent mutation in the mature protein, the tertiary structure of the protein is not altered, and a premature stop codon has not been introduced into the protein (that would be a nonsense mutation, not a silent mutation). Since the protein amino acid sequence is initially the same, an alternative start site for transcription has not been created, nor does a simple base change lead to an inhibition of DNA replication.
Category:
Biochemistry
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