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Hello, my name is Professor Eamonn Maher, I'm professor of
medical genetics and genomic medicine at the University of Cambridge.
I'm going to give a lecture on the mechanisms of human genetic disease.
Throughout this Human Genetics course,
you will have encountered many different genetic disorders that are
caused by a wide variety of genetic alterations.
These disorders have in common that
the associated genetic alterations result, in most cases,
in altered expression or function of the protein product of the relevant gene,
which then directly or indirectly leads to
pathophysiological changes that result in disease.
The aim of this lecture is to provide
selected examples of the links between different types of
genetic and epigenetic alterations, and the diversity of ways in which
they can impact protein function and lead to human genetic disease.
Given that there are thousands of rare genetic disorders,
it is of course not possible to provide
a detailed comprehensive overview of
the molecular mechanisms of all types of human genetic disease,
but I hope that the selected examples will provide some insights into this topic.
Given that this is a large complex topic, I propose to give
individual examples of genetic disorders to illustrate more general points,
and also refer you to other relevant lectures in the series.
Looking at loss-of-function variants and their role in human disease,
in fact the majority of rare genetic disorders described to date
result from loss-of-function pathogenic variants,
that may partially or completely inactivate the gene product.
The mechanisms by which genetic variants result in loss of protein
function are many and variable, and include large-scale genomic deletions
that can involve multiple genes, down to smaller single-exon deletions that may result in
the protein reading frame being shifted and
a truncated protein, or an in-frame loss of protein sequence.
Smaller genetic variants (such as nonsense and frameshift mutations that result in
a premature stop codon) can result in disease
by producing proteins that lack key functional domains,
or they may result in nonsense-mediated
mRNA decay, so that no protein is produced from the mutated allele.
Splicing mutations may, like exonic deletions,
result in truncated proteins or proteins in which specific residues are deleted.
The effect of pathogenic missense variants can be variable,
they may have a loss-of-function effect because the
missense substitution impairs the structure
or function of a key functional domain in the protein.
Or they may have an overall effect on protein stability, by abolishing
an intramolecular bond critical for the three-dimensional structure of the protein.
In addition, missense variants near exon-intron boundaries may disrupt splicing.
In many diseases caused by loss-of-function mutations,
both truncating mutations and missense mutations may be reported.
However, if only pathogenic missense mutations are described,
it could be that the loss-of-function results in
embryonic lethality or causes another phenotype, or that
missense mutations may not be disease-causing through
a straightforward loss-of-function effect, and some of
the other genetic mechanisms that are covered later on in this lecture
(for example, dominant negative effects) could be operating.
Chromosomal rearrangements such as translocations, inversions,
or duplications may cause disease by loss-of-function effects if
the rearrangement breakpoints are intragenic and disrupt normal transcription.