Biology Reference
In-Depth Information
devoted to discussing mutational mechanisms in evolution, it is pertinent to
devote at least some space here to summarizing briefly what is known of muta-
tional mechanisms underlying human genetic disease.
In general, there are three types of mutation that give rise to an inherited dis-
ease: (i) mutations which lead to a loss of function, (ii) mutations which lead to a
gain of function that is deleterious, and (iii) dominant negative mutations that
adversely affect protein subunit activity or assembly. Characterized gene muta-
tions causing genetic disease have been found to occur within coding sequences,
untranslated sequences, promoter and locus control regions, in splice junctions,
within introns and in polyadenylation sites [reviewed in detail by Cooper and
Krawczak, 1993; see also the
Human Gene Mutation Database
at
http://www.uwcm.ac.uk/uwcm/mg/hgmd0.html
, an information resource which
currently contains details of >18 500 different mutations in >900 different genes;
Cooper
et al
., 1998]. Indeed, they may interfere with any stage in the pathway of
expression from gene to protein product.
Table 1.2
presents a basic classificatory system of mutation types by reference to
the nature and position of the gene lesion and the stage in the expression pathway
Table 1.2.
A classification of types of mutation found to cause human single gene defects
through either reduced synthesis of a normal protein or normal synthesis of an abnormal
protein
(a)
Reduced synthesis of a normal gene product
Defect in
Promoter function
Binding of positive regulatory protein reduced or abolished
Binding of negative regulatory protein increased
Gene structure
Deletions (frameshift)
Insertions, duplications, inversions (frameshift).
RNA processing
Mutations in transcriptional initiation site causing failure to
stability
initiate transcription
Splice junction mutations resulting in exon skipping and/or
cryptic splice site utilization
Activation of cryptic splice sites
Polyadenylation/cleavage signal mutations
Mutations in 3 untranslated region
Translation
Initiation and termination codon mutations
Mutations in 5 untranslated region
Nonsense mutations
(b)
Synthesis of structurally/functionally abnormal gene product
Gene structure defect resulting in
Shortened gene product
Deletions (in-frame), nonsense mutations
Fusion genes
Deletions involving two linked genes
Elongated gene product
Insertions, duplications (in-frame)
Termination codon mutations
Defective post-translational
Missense mutations
modification or processing,
instability of protein product,
impaired assembly/secretion,
altered substrate/cofactor/
receptor affinity.
