section 24.6

DNA Mutation

561

TABLE 24-4

Inherited Diseases Involving Repeated Trinucleotides That Are Present in an Excessive Number o f Copies

*

Disease

Trinucleotide repeat

Symptoms

Fragile X syndrome

CGG

5-54 unaffected

60-230 carriers

230-4000 affected

Mental retardation

Huntington’s disease

CAG

11-30 unaffected

36-121 affected

Chorea, progressive dementia, death

Myotonic dystrophy

CTG

Muscle weakness, myotonia

Spinocerebellar ataxia Type 1

CAG

19-36 unaffected

40-81 affected

Ataxia, dysarthria, rigidity, abnormal eye movements

Fredreich’s ataxia

GAA

7-22 unaffected

200-900 affected

Ataxia, dysarthria, hypertropic cardiomyopathy, diabetes

Machado-Joseph disease

CAG

12-37 unaffected

61-84 affected

Spasticity, dystonia

*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

about

2 0

% of all mental retardation; about

1

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 (

FMR1

) 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-

neurologic

diseases

including

Huntington’s

disease,

myotonic

dystrophy,

Friedreich’s

ataxia,

and

others

(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

replication.

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