Unstable mutations
It has generally been assumed that mutant alleles causing
mendelian disorders are transmitted unchanged from parent to
child. In 1991 the discovery of unstable trinucleotide repeat
expansion mutations identified a novel genetic mechanism
underlying a number of important disorders.
Saturday, April 11, 2009
Several genes
Several genes are known to contain regions of trinucleotide
repeats. The number of repeats varies from person to person in
the general population, but within the normal range these
repeats are stably transmitted. When the number of repeats is
increased beyond the normal range, this region becomes
unstable with a tendency to increase in size when transmitted to
offspring. In some conditions there is a clear distinction
between normal and pathological alleles. In others, the
expanded alleles may act either as premutations or as full
pathological mutations. Premutations do not cause disease but
are unstable and likely to expand further when transmitted to
offspring. Once the repeat reaches a certain size it becomes a
full mutation and disease will occur. Since the age at onset and
severity of the disease correlate with the size of the expansion,
this phenomenon accounts for the clinical anticipation that is
seen in this group of conditions, where age at onset decreases
in successive generations of a family. There is a sex bias in the
transmission of the most severe forms of some of these
disorders, with maternal transmission of congenital myotonic
dystrophy and fragile X syndrome, but paternal transmission of
juvenile Huntington disease.
repeats. The number of repeats varies from person to person in
the general population, but within the normal range these
repeats are stably transmitted. When the number of repeats is
increased beyond the normal range, this region becomes
unstable with a tendency to increase in size when transmitted to
offspring. In some conditions there is a clear distinction
between normal and pathological alleles. In others, the
expanded alleles may act either as premutations or as full
pathological mutations. Premutations do not cause disease but
are unstable and likely to expand further when transmitted to
offspring. Once the repeat reaches a certain size it becomes a
full mutation and disease will occur. Since the age at onset and
severity of the disease correlate with the size of the expansion,
this phenomenon accounts for the clinical anticipation that is
seen in this group of conditions, where age at onset decreases
in successive generations of a family. There is a sex bias in the
transmission of the most severe forms of some of these
disorders, with maternal transmission of congenital myotonic
dystrophy and fragile X syndrome, but paternal transmission of
juvenile Huntington disease.
onset neurodegenerative disorders
A number of late onset neurodegenerative disorders (for
example Huntington disease and spinocerebellar ataxias) are
associated with expansions of a CAG repeat sequence in the
coding region of the relevant gene, that is translated into
polyglutamine tracts in the protein product. These mutations
confer a specific gain of function and cause the protein to form
intranuclear aggregates that result in cell death. There is
usually a clear distinction between normal- and disease-causing
alleles in the size of their respective number of repeats and no
other types of mutation are found to cause these disorders.
example Huntington disease and spinocerebellar ataxias) are
associated with expansions of a CAG repeat sequence in the
coding region of the relevant gene, that is translated into
polyglutamine tracts in the protein product. These mutations
confer a specific gain of function and cause the protein to form
intranuclear aggregates that result in cell death. There is
usually a clear distinction between normal- and disease-causing
alleles in the size of their respective number of repeats and no
other types of mutation are found to cause these disorders.
other disorders
In other disorders (for example fragile X syndrome and
Friedreich ataxia) very large expansions occur, which prevent
transcription of the gene, and act recessively as loss of function
mutations. Other types of mutations occur occasionally in these
genes resulting in the same phenotype. In myotonic dystrophy the
pathological mechanism of the expanded repeat is not known. It
is likely that the expansion affects the transcriptional process of
several neighbouring genes. Juvenile myoclonus epilepsy is due to
the expansion of a longer repeat region (CCCCGCCCCGCG)
normally present in two to three copies in the gene promoter
region, expanding to 40 or more repeats in mutant alleles.
Trinucleotide repeat expansions have also been found in other
conditions (for example polysyndactyly from HOXD13 mutation),
where the pathological expansion shows no instability.
Friedreich ataxia) very large expansions occur, which prevent
transcription of the gene, and act recessively as loss of function
mutations. Other types of mutations occur occasionally in these
genes resulting in the same phenotype. In myotonic dystrophy the
pathological mechanism of the expanded repeat is not known. It
is likely that the expansion affects the transcriptional process of
several neighbouring genes. Juvenile myoclonus epilepsy is due to
the expansion of a longer repeat region (CCCCGCCCCGCG)
normally present in two to three copies in the gene promoter
region, expanding to 40 or more repeats in mutant alleles.
Trinucleotide repeat expansions have also been found in other
conditions (for example polysyndactyly from HOXD13 mutation),
where the pathological expansion shows no instability.
Uniparental disomy
Another unusual mechanism causing human disease is that of
uniparental disomy (UPD), where both copies of a particular
chromosome are inherited from one parent and none from the
other. Usually, UPD arises by loss of a chromosome from a
conception that was initially trisomic (trisomy rescue). The
resulting zygote could contain one chromosome from each
parent (normal), two identical chromosomes from one parent
(isodisomy) or two different chromosomes from one parent
(heterodisomy). Occasionally UPD may arise by fertilisation of
a monosomic gamete followed by duplication of the
chromosome from the other gamete (monosomy rescue). This
mechanism results in uniparental isodisomy. Theoretically, UPD
could also arise by fertilisation of a momosomic gamete with a
disomic gamete, resulting in either isodisomy or heterodisomy.
uniparental disomy (UPD), where both copies of a particular
chromosome are inherited from one parent and none from the
other. Usually, UPD arises by loss of a chromosome from a
conception that was initially trisomic (trisomy rescue). The
resulting zygote could contain one chromosome from each
parent (normal), two identical chromosomes from one parent
(isodisomy) or two different chromosomes from one parent
(heterodisomy). Occasionally UPD may arise by fertilisation of
a monosomic gamete followed by duplication of the
chromosome from the other gamete (monosomy rescue). This
mechanism results in uniparental isodisomy. Theoretically, UPD
could also arise by fertilisation of a momosomic gamete with a
disomic gamete, resulting in either isodisomy or heterodisomy.
Uniparental disomy
Uniparental disomy may have no clinical consequence by
itself. It is occasionally detected by the unmasking of a recessive
disorder for which only one parent is a carrier when there is
isodisomy for the parental chromosome carrying such a
mutation. In this rare situation the child would be affected by a
recessive disorder for which the other parent is not a carrier.
Recurrence risk for the disorder in siblings is extremely low
since UPD is not likely to occur again in another pregnancy.
The other situation in which UPD will have an effect is
when the chromosome involved contains one or more
imprinted genes, as described in the next section.
itself. It is occasionally detected by the unmasking of a recessive
disorder for which only one parent is a carrier when there is
isodisomy for the parental chromosome carrying such a
mutation. In this rare situation the child would be affected by a
recessive disorder for which the other parent is not a carrier.
Recurrence risk for the disorder in siblings is extremely low
since UPD is not likely to occur again in another pregnancy.
The other situation in which UPD will have an effect is
when the chromosome involved contains one or more
imprinted genes, as described in the next section.
Imprinting
It has been observed that some inherited traits do not conform
to the pattern expected of classical mendelian inheritance in
which genes inherited from either parent have an equal effect.
The term imprinting is used to describe the phenomenon by
which certain genes function differently, depending on
whether they are maternally or paternally derived. The
mechanism of DNA modification involved in imprinting
remains to be explained, but it confers a functional change
in particular alleles at the time of gametogenesis determined
by the sex of the parent. The imprint lasts for one generation
and is then removed, so that an appropriate imprint can be
re-established in the germ cells of the next generation.
to the pattern expected of classical mendelian inheritance in
which genes inherited from either parent have an equal effect.
The term imprinting is used to describe the phenomenon by
which certain genes function differently, depending on
whether they are maternally or paternally derived. The
mechanism of DNA modification involved in imprinting
remains to be explained, but it confers a functional change
in particular alleles at the time of gametogenesis determined
by the sex of the parent. The imprint lasts for one generation
and is then removed, so that an appropriate imprint can be
re-established in the germ cells of the next generation.
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