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Several disorders,
such as Huntington disease,
spinal and bulbar muscular atrophy, myotonic dystrophy, and fragile X syndrome,
are characterized by triplet repeat mutations.
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Triplet repeat mutations in human disease.Science.
1992 May 8;256(5058):784-9.
Triplet repeats
are the sites of mutation in three human heritable disorders, spinal
and bulbar muscular atrophy (SBMA), fragile X syndrome, and myotonic
dystrophy (DM). These repeats are GC-rich and highly polymorphic in
the normal population. Fragile X syndrome and DM are examples of
diseases in which premutation alleles cause little or no disease in
the individual, but give rise to significantly amplified repeats in
affected progeny. This newly identified mechanism of mutation has,
so far, been identified in two of the most common heritable
disorders, fragile X syndrome and DM, and one rare disease, SBMA.
Genes with triplet
repeats: a new class of mutations causing neurological diseases.Biomed
Pharmacother. 1994;48(5-6):191-7.
Microsatellites, simple tamdem repeats of 2 to 4 nucleotide
sequences, are widely distributed throughout the genome.
Trinucleotide repeats are found every 300 to 500 kb. Recently, a new
type of mutation was described involving a specific expansion of
triplets within or in close proximity to a gene. Expanded triplets
have been found in the genes causing six different neurological
disorders: fragile X syndrome (FRAXA), spinal and bulbar muscular
atrophy (SBMA), myotonic dystrophy (DM), Huntington's disease (HD),
spinocerebellar ataxia type 1 (SCA1), and
dentato-rubra-pallidoluysian atrophy (DRPLA). These neurological
disorders have in common a variable age of onset and clinical
severity, as well as a decrease in the age of onset over
generations, known as anticipation. These unusual characteristics
are related to the observation that expanded repeats are unstable
both in meioses and mitoses. A younger age of onset and an increase
in severity correlate with a higher number of repeats.
Interestingly, particular haplotypes are in disequilibrium with the
mutation for FRAXA, DM and HD, suggesting instability for selected
chromosomes. How expanded triplets affect the expression and the
function of genes is still unknown. Since neurodegenerative
disorders are often variable in age of onset and clinical severity,
the list of expanding triplet mutations should increase in the very
near future. |
In these mutations, there is long
repeated sequence of three nucleotides, and more affected sequences
share the nucleotides guanine (G) and cytosine (C).
Fragile X syndrome:
The fragile X
syndrome is the most common cause of familial intellectual disability.
In 1991, after identification of the fragile X mental retardation (FMR1)
gene, the cytogenetic marker (a fragile site at Xq27.3) became replaced
by molecular diagnosis.
The fragile X
syndrome was one of the first examples of a "novel" class of disorders
caused by a trinucleotide repeat expansion.
The identification
of the 'fragile-X mental retardation' gene disclosed a novel
genetic mechanism: an intergenerational instable
cytosine-guanine-guanine (CGG) repeat leading to the absence of FMR1
protein above a threshold of 200 repeats and, subsequently, leading to
familial mental retardation.
In normal individuals, the average number of
repeats is 29, where as affected individuals have 230 to 4000 repeats.
In between are those with permutations characterized by 50 to 230 CGG
repeats.
| The
fragile X syndrome.
J Med Genet. 1998 Jul;35(7):579-89.
The fragile X
syndrome is characterised by mental retardation, behavioural
features, and physical features, such as a long face with large
protruding ears and macro-orchidism. In 1991, after identification
of the fragile X mental retardation (FMR1) gene, the cytogenetic
marker (a fragile site at Xq27.3) became replaced by molecular
diagnosis. The fragile X syndrome was one of the first examples of a
"novel" class of disorders caused by a trinucleotide repeat
expansion. In the normal population, the CGG repeat varies from six
to 54 units. Affected subjects have expanded CGG repeats (>200) in
the first exon of the FMR1 gene (the full mutation). Phenotypically
normal carriers of the fragile X syndrome have a repeat in the 43 to
200 range (the premutation). The cloning of the FMR1 gene led to the
characterisation of its protein product FMRP, encouraged further
clinical studies, and opened up the possibility of more accurate
family studies and fragile X screening programmes. |
In carrier females, the permutations undergo amplification
during oogenesis, resulting in full mutations that are then passed on to
their progeny. Because the
mutations are
carried on the X chromosome,
this is an X-linked recessive disorder.
Because permutations are silent,
and they are amplified only during oogenesis in carrier females, however
the transmission pattern differs from classic X-linked disorders.
Thus
carrier males with permutations do not have any symptoms, approximately
50% of carrier females are affected.
The molecular basis of fragile X
syndrome is not clear. Presence of greater than 230 CGG repeats causes
transcriptional suppression of the FMR-1 gene.
Clinically,
affected males have severe mental retardation.
80%
patients have an enlarged
testis.
Other physical
features that may be present, include an elongated face,
large protruding
ears
and large
mandible.
The clinical features worsen with each
successive generation, due to amplification of nucleotide repeats during oogenesis. This phenomenon is called
anticipation.
In addition to fragile X syndrome, about
10% other disorders have been associated with a similar type of
mutation.
In all cases, neurodegenerative changes
dominate the clinical picture.
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Fragile X syndrome (review).Int
J Mol Med. 1999 Jun;3(6):639-45.
Fragile X
syndrome is the most common form of inherited mental retardation
currently known, associated with a wide range of developmental
disabilities in both males and females, caused by a large expansion
of a (CGG)n repeat in the first exon of the FMR1 gene. Fragile X
syndrome occurs in all racial and ethnic groups, and it is a
condition of major epidemiological importance among mentally
handicapped males. Therefore, this disease must be considered in the
differential diagnosis of any child with developmental delay, mental
retardation or learning disability. The fragile X syndrome is due to
the shutdown of the FMR1 gene transcription, and the pathogenesis of
this syndrome is a consequence of absence of the protein product of
the FMR1 gene (FMRP). Since the great majority of fragile X patients
have the same type of mutation in a specific location of the gene,
molecular analysis is extremely accurate for diagnosis of the
disease, and important for genetic counseling of family members.
Others genetic disorders are also caused by expanded trinucleotide
repeats. |
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