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 Trinucleotide,
or triplet, repeats consist of 3 nucleotides consecutively repeated (e.g.,
CAG CAG CAG CAG) within a region of DNA. All possible combinations of
nucleotides are known to exist as triplet repeats, although some are more
common than others. These repeated sequences are found both within gene
boundaries and in the large stretches of DNA that lie between genes. If
the triplet repeats lie within a gene, they may be found within the flanking
upstream promoter region, within exons, or within introns. If they lie
within exons, they may be present in the sequence that will be translated
into protein. In that case, the repeat encodes a series of identical amino
acids. The triplets may also occur at the 5' or 3' untranslated portion
of the transcript. The different regions in which triplet repeats may
lie are summarized in Figure
1.
Thousands
of trinucleotide repeats exist throughout the human genome. Many are the
same length in all individuals, while others are of variable length. The
variable, or polymorphic, repeats are almost always transmitted without
change in length from one generation to the next. However, some do change
in length when passed on, and when that occurs, the gene is often disrupted.
This mutational type, first discovered in 1991, was termed a dynamic or
expansion mutation. Over the past 8 years, more than a dozen diseases
caused by trinucleotide repeat expansions have been identified. The discovery
of this class of mutations has led to great excitement in the field of
genetics, since expansion mutations often have properties contrary to
the conventional wisdom of mendelian genetics.
The currently known expansion mutation disorders fall into 3 general groups
(Fig.
1). Eight diseases are caused by expanded CAG
repeats encoding the amino acid glutamine. The best known and most thoroughly
characterized member of this group is Huntington disease. The other members
include spinocerebellar ataxia types 1, 2, 3, 6, and 7; dentatorubral-pallidoluysian
atrophy; and spinal and bulbar muscular atrophy. The repeated expansion
occurs in different genes for each of these 8 disorders. However, for
this group of disorders, the number of repeats at which the expansion
is sufficient to cause disease is similar, typically about 40 triplets.
Each disease within this first group is characterized by neurodegeneration
in a particular set of cortical and subcortical brain regions. The pathology
appears to result from neurotoxic properties of the excessively long stretches
of glutamine residues encoded by the CAG repeat expansions. The clinical
manifestations of these diseases, as exemplified by Huntington disease,
may include abnormalities of voluntary and involuntary movement; dementia;
affective, psychotic, or obsessive-compulsive symptoms; apathy; irritability;
and other less specific personality changes.
A second group of illnesses caused by relatively short repeat expansions
consists of mostly developmental disorders. The number of repeats in some
of these illnesses is as few as 1 or 2 additional triplets, resulting
in proteins with only a few more amino acid residues than is normally
found. However, these additional extra amino acids are sufficient to disrupt
the normal function of the protein. One example, synpolydactyly, is characterized
by abnormal skeletal patterning. It is caused by 7 to 10 additional GCN
triplets (in which N is any of the 4 base pairs). These additional codons
will add the amino acid alanine into the protein sequence of the transcription
factor HOXD13.
Cleidocranial dysplasia is another disorder of skeletal development that
is caused by the presence of approximately 10 GCN triplets. In this case,
10 alanines are added to the protein CBFA1 (core-binding factor A1) that
encodes a subunit of another regulatory transcription factor. Oculopharyngeal
muscular dystrophy is caused by expansion of a GCG repeat that places
additional alanine residues in the PABP2 (polyA binding protein
2) gene. It is interesting that this disease can be either autosomal recessive
or autosomal dominant, depending on the repeat length. Finally, the normal
repeat of the cartilage oligomeric matrix protein contains 5 GAC triplets
encoding the amino acid aspartate. If the repeat contracts by a single
triplet or expands by 1 or 2 triplets, the result is 1 of 2 related developmental
disorders of the skeleton, pseudoachondroplasia or multiple epiphyseal
dysplasia.
A third and more heterogeneous group of disorders results from repeat
expansions outside of the protein coding region. These expansions are
characterized by their large size, in some cases repeating hundreds or
even thousands of times. The prototypical disease of this type is fragile
X syndrome, caused by the expansion of a CGG repeat in the 5' untranslated
region of the gene FMR1 (fragile X mental retardation 1). There
remains debate as to exactly how the large repeat leads to disease. One
proposed mechanism is that the expansion becomes chemically modified through
a process termed methylation and that this interferes with normal transcription
machinery. The net effect of the large expansion is a decrease or absence
of any transcription from the FMR1 gene, with an accompanying decrease
in functional protein.
The FMR1 gene is on the X chromosome. Males with the mutation lack
a second, normal copy of the gene. These children have a more severe phenotype
than females who have a normal FMR1 gene on their second X chromosome.
Affected males typically have dysmorphic facial features, gonadal hypertrophy,
mental retardation, and psychiatric symptoms, including some of the signs
and symptoms typically seen in autism. Females with one normal and one
expanded repeat have a milder phenotype and typically show milder cognitive,
affective, and social difficulties. In both males and females, there is
a rough correlation between the length of the repeat and the severity
of the illness. A second triplet repeat disorder that causes mental retardation
was recently discovered nearby on the X chromosome and is caused by the
expansion of a GCC repeat in its 5' untranslated region.
Several other disorders in this third group have expansions outside the
protein-coding region. A 3' untranslated CTG repeat causes myotonic dystrophy.
With extreme expansions, myotonic dystrophy can be a life-threatening
disorder with prominent cognitive impairment. Friedreich ataxia is a recessive
disorder with childhood onset and multiple abnormalities including prominent
cerebellar signs. It is usually the result of a long GAA repeat expansion
in an intron of the gene frataxin. An expansion of a dodecamer
repeat (CCCCGCCCCGCG) in the promoter region of the gene cystatin B
is the most common genetic mutation causing episodic myoclonic epilepsy
type 1. This illness is characterized by its childhood onset, seizures,
myoclonus, dementia, and affective symptoms. Expansion of the 5' untranslated
CCG repeat in the proto-oncogene CBL2 can result in deletion of
the terminal arm of chromosome 11, giving rise to a contiguous gene syndrome
with multiple developmental abnormalities. Spinocerebellar ataxia type
8, unlike the other spinocerebellar ataxias in which the repeat lies within
the protein-coding region, results from an CTG expansion in the 3' untranslated
region.
The discovery of triplet repeat mutations solved a long-standing enigma
in genetics. From early in this century, it was noticed that some diseases
have an earlier age of onset or a more severe phenotype with each successive
generation in an affected family. As there was no biological explanation
for this phenomenon, known as anticipation, many considered it an artifact
of subject ascertainment. Anticipation in some of these disorders can
be dramatic. In myotonic dystrophy, for example, repeats just above the
threshold for illness may result only in cataracts late in life. Within
2 or 3 generations, the progeny of such individuals may have remarkably
long repeats, resulting in fatal congenital disease.
It is now clear that anticipation is not an artifact and can be explained
by the unique properties of expansion mutations. The molecular basis for
anticipation is that most repeats long enough to cause disease are unstable
and have a tendency to get longer with each successive generation. The
longer the expansions are, the earlier symptoms arise or the more severe
these symptoms become. Two mechanisms have been proposed to explain these
findings. In some disorders, the expansion produces more of a toxic gene
product. This is likely to occur in Huntington and related diseases. For
other repeat disorders, the expansion results in less transcription from
the affected gene, and as a consequence, less of the functional protein
is produced. Fragile X is an illness that exemplifies this type of mechanism.
Finally, for some disorders, such as myotonic dystrophy, the expansion
occurs in the 3' untranslated region and the mechanisms to explain the
increase in symptoms are yet to be discovered.
Other unusual genetic phenomena have been observed in triplet repeat disorders.
All are attributable to the variability in repeat length that is found
among affected individuals. Examples include monozygotic twins who are
discordant for a particular illness, presumably as a consequence of postzygotic
changes in repeat length. Others include skipped generations (a consequence
of incomplete penetrance), disappearance of disease from a branch of a
family (reversion of a repeat to a length below the disease threshold),
and seemingly sporadic cases of a disease (expansion of a repeat from
below to above disease threshold).
What is the relevance of repeat expansions to child and adolescent psychiatry?
As was mentioned earlier, many of the known repeat expansion disorders
present as congenital or childhood disorders that often have prominent
neurological as well as psychiatric features. Fragile X, the most common
famiial cause of mental retardation, is certainly a striking example of
this, as is juvenile Huntington disease. Understanding the unusual genetics
of these disorders is an important factor in establishing an accurate
diagnosis and prognosis and is essential in providing counseling to affected
families. Both Huntington disease and fragile X syndrome will be reviewed
in the next 2 columns in this Journal.
Repeat expansion disorders may also be of relevance for other psychiatric
disorders. Most interestingly, anticipation has been detected in bipolar
disorder and schizophrenia. In autism, anticipation per se has been less
thoroughly addressed, but it appears that the parents of some affected
children have milder symptoms, suggesting an increase in phenotypic severity
over successive generations. Interpretation of these findings, however,
remains difficult as the age-of-onset estimates are subject to multiple
biases. Even if anticipation is present, it may be explained by several
biological mechanisms in addition to repeat expansion. The question of
whether or not trinucleotide expansions contribute to the genetic susceptibility
to psychiatric disorders will be answered only after a systematic search
for such mutations is conducted.
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