Inherited Diseases Involving Repeated Trinucleotides That Are Present in an Excessive Number o f Copies
Fragile X syndrome
Chorea, progressive dementia, death
Muscle weakness, myotonia
Spinocerebellar ataxia Type 1
Ataxia, dysarthria, rigidity, abnormal eye movements
Ataxia, dysarthria, hypertropic cardiomyopathy, diabetes
*The extent of the repeated triplet nucleotide usually determines the severity of the disease and the age of onset. These diseases may be caused
by slippage of the DNA polymerase during replication that increases the length of the repeated triplet from generation to generation. The
patterns o f inheritance are: Fragile X syndrome (X-linked); Huntington’s disease, myotonic dystrophy, Spinocerebellar ataxia Type I, Machado-
Joseph disease (autosomal dominant); Fredreich’s ataxia (autosomal recessive).
the X chromosome and the associated inherited disorder
fragile X syndrome.
This particular mutation accounts for
% of all mental retardation; about
in 1500 boys
and 1 in 2500 girls are bom with fragile X syndrome.
Although fragile X syndrome is classified a Mendelian
dominant sex-linked disorder, it does not behave as a clas-
sically dominant gene inherited disease. Only about 80%
of males and 35% of females who carry the mutation and a
fragile site suffer from mental retardation. For many years
it remained a mystery how both men and women could
carry a fragile X chromosome and be unaffected.
In the 1990s, the molecular explanation for fragile X
syndrome was revealed. The gene responsible for frag-
ile X syndrome (
) was found to contain a repeat
of the trinucleotide CGG. In unaffected individuals, the
number of CGG repeats ranges from about 5 to 54 copies.
In mentally retarded individuals, the number of CGG re-
peats is dramatically increased to hundreds or thousands of
copies. When the CGG repeat exceeds 230, the DNA be-
comes abnormally methylated in that region and the gene
becomes nonfunctional. Presumably the amplification of
the CGG repeat occurs during DNA replication in germ
cells prior to meiosis perhaps due to “stuttering” of the
DNA polymerase as it reads the repeating trinucleotides.
Why amplification of the CGG repeats occurs in some X
chromosomes but not others and in some individuals and
not others is unresolved.
Triplet repeats account for a growing list of muscular-
(Table 24-4). Triplet repeats represent an entirely new
class of mutations. They are not caused by any external
mutagenic agent but are generated during normal DNA
Fragile sites are chromosomal regions that are prone
to breakage during chromosome movement or recombi-
nation; fragile sites can be visualized by a variety of
cytological techniques and dyes that bind to metaphase
chromosomes. Fragile sites are relatively common in chro-
mosomes and there is a growing suspicion that they may
play a greater role in disease, especially cancer, than pre-
viously thought. The chromosomes in many tumor cells
exhibit fragile sites that are not present in normal cells.
What is not yet clear is whether a fragile site initiates the
conversion of a normal cell to a cancer cell or is merely
the consequence of the altered growth properties of the