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7.2 Molecular Mechanisms That Alter DNA Sequence 229

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Trinucleotide Repeat Diseases: Huntington Disease and Fragile X Syndrome
The approximately 20 known neurogenerative diseases caused Figure A Huntington disease: a polyQ repeat disease.
by genes with unstable trinucleotide (triplet) repeats fall into two The HD gene has a run of CAG repeats that specify glutamines
categories: polyQ diseases and non-polyQ diseases (where Q is (Qs) in the open reading frame (ORF). HD disease alleles direct the
the symbol for the amino acid glutamine). In polyQ disease genes, synthesis of a mutant, toxic HD protein with an expanded polyQ
the repeated triplet is always CAG, while in non-polyQ disease region. Pre-mutation alleles with an intermediate number of CAGs
genes, the trinucleotide repeat may be either CGG, CTG, GCC, or produce a normally functioning protein, but the allele is unstable.
GAA. The two types of triplet repeat diseases are distinguished PolyQ disease: Huntington disease
by the effect of the repeat sequence on gene function. In polyQ CAG
diseases, a disease allele with too many triplet repeats encodes 36–120 mutant
an abnormal protein. Non-polyQ disease alleles encode either no CAG 29–35 pre-mutation
protein or decreased protein amounts. The differences in the two CAG 6–28 normal
classes of triplet repeat diseases are illustrated by the best-
known example of each: Huntington disease, a polyQ disease; HD gene ORF
and fragile X syndrome, a non-polyQ disease. Beginning of gene PolyQ region
Huntington disease affects about 1 in 10,000 people
worldwide. The symptoms usually start at about 40 years of
age and include muscle coordination difficulties, cognitive de-
cline, and psychiatric problems. You saw in Chapter 2 that
Huntington disease is inherited through autosomal dominant Figure B Fragile X syndrome: a non-polyQ repeat
+
mutant alleles (HD). While normal HD alleles have between 6 disease. The FMR-1 gene has a run of CGG repeats in the 5′
and 28 CAG repeats, HD disease alleles have an expanded untranslated region (5′ UTR) outside the ORF. FMR-1 disease
repeat region that has 36 or more CAG repeats. The run of alleles have an expanded repeat number, and this prevents
CAGs in the HD gene are in the open reading frame, or ORF, synthesis of the gene’s protein product. Pre-mutation alleles with
that contains the actual instructions to build a protein from its an intermediate number of CGGs make normal amounts of protein,
constituent amino acids. but these alleles are unstable.
Each CAG specifies that the amino acid glutamine (Q) Non-polyQ disease: fragile X syndrome
should be added to the HD protein, so the normal protein has
6 to 28 Q amino acids in a row in its so-called polyQ region CGG 200–4000 mutant
(Fig. A). An HD allele with 36 or more repeats encodes a mutant CGG 56–200 pre-mutation
HD protein with an expanded polyQ region that is toxic to CGG 6–55 normal
nerve cells. (Proteins encoded by pre-mutation alleles function
normally but the alleles have an unstable repeat number.) FMR-1 gene ORF
5' UTR
Scientists do not yet understand the normal function of HD in Beginning of gene
nerve cells or the reason why the mutant HD protein is toxic.
PolyQ disease alleles like HD are called gain-of-function
mutants because they specify proteins whose functions are
qualitatively different from those of the corresponding wild-type expanded repeats in non-polyQ disease genes generally prevent
protein. Typical for many gain-of-function mutants, polyQ disease protein production, and so non-polyQ disease genes are loss-of-
alleles show dominant inheritance because the mutant polyQ function alleles. Because females heterozygous for the disease
proteins are toxic even in the presence of the normal proteins. allele have at least some disease symptoms most of the time,
Non-polyQ diseases are exemplified by fragile X syn- fragile X syndrome shows X-linked dominant inheritance with in-
drome, a leading cause of inherited intellectual disability, affect- complete penetrance and variable expressivity. Other non-polyQ
ing about 1 in 4000 males and 1 in 8000 females. The disease disease alleles may show either dominant or recessive inheri-
is caused by expansion of a CGG repeat region in an X-linked tance patterns, depending on whether two doses or one dose of
gene called FMR-1 (for fragile X mental retardation-1). the normal gene product is required to avoid disease symptoms.
The CGGs of FMR-1 are located in a region of the gene out- The triplet repeat diseases illustrate two fundamental prin-
+
side of the ORF called the 5′ UTR (Fig. B). Normal FMR-1 genes ciples regarding mutations. First, mutations may affect either
have between 6 and 55 CGG repeats; expansion of the repeat the nature of the gene product (polyQ diseases) or the amount
number to 200 CGGs or more results in an FMR-1 disease allele of the gene product (non-polyQ diseases). Second, certain DNA
that cannot produce the FMR-1 protein. Without FMR-1 protein, sequences can mutate at surprisingly high frequencies in spe-
nerve cells cannot properly form connections called synapses. cial circumstances, as seen by pre-mutation alleles for either
A feature common to all non-polyQ diseases is that the trip- Huntington disease or fragile X syndrome. These two principles
lets are located in a part of the gene outside of the ORF. The will be important themes in subsequent chapters.