Mutational spectrum

Describing the mutational basis of a genetic disorder is an initial step in understanding how the disorder arises; what the DNA sequence change does to the protein gives a clue to the protein's function (if unknown) and to the pathogenesis of the condition. Analysis of mutants causing dementia, isolated by positional molecular cloning, are an example.

The presenilins are ubiquitously expressed transmembrane proteins of unknown function, in which mutations give rise to rare forms of inherited Alzheimer's disease/!.6,! and !8,30) All but one of the many mutations that have been described are mis-sense mutations. Why are there no frame-shift or non-sense mutants? Recall that mis-sense mutants alter an amino acid in the protein and therefore can alter its function. Presumably therefore the mutations in presenilin result in a gain of function, although what that may be is unknown. One clue comes from looking at where the mutations occur within the protein, to discern whether some parts of the molecule are more frequently involved than others. The distribution of mutations in the presenilins is indeed non-random; they occur at residues which are the same in both presenilin genes, lying on one side of the a helix in transmembrane domains, predominantly in exon 8. Thus the mutational spectrum highlights key residues for understanding the protein's functions.(3,32>

Where a gene's function is known, the distribution of mutations may point out the likely pathogenesis. For example, mutations in the tau gene are now known to cause frontotemporal dementia with parkinsonism (Pick's disease).(3334ยป The most common mutation occurs in the 5' splice site of exon 10, resulting in overproduction and accumulation of one form of tau; mutations in other regions of the gene lead to accumulation of a different form of the protein. The position of the mutations in tau indicate that they cause disruption of tau microtubule binding, which may cause cell death by the degeneration of microtubules or through an increase in unbound tau.

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