Expansions Affecting Coding Regions

Spinobulbar muscular atrophy (Kennedy disease) AR Xq13-21 Androgen receptor (AR) CAG 9–36 38–62

Huntington disease HD 4p16.3 Huntingtin CAG 6–35 36–121

Dentatorubral-pallidoluysian atrophy (Haw River

syndrome)

DRPLA 12p13.31 Atrophin-1 CAG 6–35 49–88

Spinocerebellar ataxia type 1 SCA1 6p23 Ataxin-1 CAG 6–44 39–82

Spinocerebellar ataxia type 2 SCA2 12q24.1 Ataxin-2 CAG 15–31 36–63

Spinocerebellar ataxia type 3 (Machado-Joseph

disease)

SCA3 (MJD1) 14q32.1 Ataxin-3 CAG 12–40 55–84

Spinocerebellar ataxia type 6 SCA6 19p13 a1A -Voltage-dependent calcium channel

subunit

CAG 4–18 21–33

Spinocerebellar ataxia type 7 SCA7 3p12-13 Ataxin-7 CAG 4–35 37–306

Figure 5-34Sites of expansion and the affected sequence in selected diseases caused by nucleotide repeat mutations. UTR, untranslated region. *Although not strictly a trinucleotide repeat

disease, progressive myoclonus epilepsy is caused, like others in this group, by a heritable DNA expansion. The expanded segment is in the promoter region of the gene.

Figure 5-35Pedigree of Leber hereditary optic neuropathy, a disorder caused by mutation in mitochondrial DNA. Note that all progeny of an affected male are normal, but all children, male

and female, of the affected female manifest disease.

Figure 5-36Diagrammatic representation of Prader-Willi and Angelman syndromes.

Figure 5-37Direct gene diagnosis: detection of coagulation factor V mutation by polymerase chain reaction (PCR) analysis. A GÕA substitution in an exon destroys one of the two Mnl1

restriction sites. The mutant allele therefore gives rise to two, rather than three, fragments by PCR analysis.

Figure 5-38Diagnostic application of PCR and Southern blot analysis in fragile-X syndrome. With PCR, the differences in the size of CGG repeat between normal and premutation give rise

to products of different sizes and mobility. With a full mutation, the region between the primers is too large to be amplified by conventional PCR. In Southern blot analysis the DNA is cut by

enzymes that flank the CGG repeat region, and is then probed with a complementary DNA that binds to the affected part of the gene. A single small band is seen in normal males, a highermolecular-

weight band in males with premutation, and a very large (usually diffuse) band in those with the full mutation.

With this background, we can discuss how RFLPs can be used in gene tracking. Figure 5-39 illustrates the principle of RFLP analysis. In this example of an autosomal recessive disease, both

of the parents are heterozygote carriers and the children are normal, are carriers, or are affected. In the illustrated example, the normal chromosome (A) has two restriction sites, 7.6 kb apart,

whereas chromosome B, which carries the mutant gene, has a DNA sequence polymorphism resulting in the creation of an additional (third) restriction site for the same enzyme. Note that the

additional restriction site has not resulted from the mutation but from a naturally occurring polymorphism. When DNA from such an individual is digested with the appropriate restriction

enzyme and probed with a cloned DNA fragment that hybridizes with a stretch of sequences between

the restriction sites, the normal chromosome yields a 7.6 kb band, whereas the other chromosome (carrying the mutant gene) produces a smaller, 6.8 kb, band. Thus, on Southern blot

analysis, two bands are noted. It is possible by this technique to distinguish family members who have inherited both normal chromosomes from those who are heterozygous or homozygous

for the mutant gene. PCR followed by digestion with the appropriate restriction enzyme and gel electrophoresis can also be used to detect RFLPs if the target DNA is of the size that can be

amplified by conventional PCR.

• Length polymorphisms: Human DNA contains short repetitive sequences of noncoding DNA. Because the number of repeats affecting such sequences varies greatly between

different individuals, the resulting length polymorphisms are quite useful for linkage analysis. These polymorphisms are often subdivided on the basis of their length into microsatellite

repeats and minisatellite repeats. Microsatellites are usually less than 1 kb and are characterized by a repeat size of 2 to 6 base pairs. Minisatellite repeats, by comparison, are larger (1 to 3

kb), and the repeat motif is usually 15 to 70 base pairs. It is important to note that the number of repeats, both in microsatellites and minisatellites, is extremely variable within a given

population, and hence these stretches of DNA can be used quite effectively to distinguish different chromosomes ( Fig. 5-40A ). Figure 5-40B illustrates how microsatellite polymorphisms

can be used to track the inheritance of autosomal dominant polycystic kidney disease (PKD). In this case, allele C, which produces a larger PCR product than allele A or B, carries the diseaserelated

gene. Hence all individuals who carry the C allele are affected. Microsatellites have assumed great importance in linkage studies and hence in the development of the human genome

map. Currently, linkage to all human chromosomes can be identified by microsatellite polymorphisms.[86]

Figure 5-39Schematic illustration of the principles underlying restriction fragment length polymorphism analysis in the diagnosis of genetic diseases.

Figure 5-40Schematic diagram of DNA polymorphisms resulting from a variable number of CA repeats. The three alleles produce PCR products of different sizes, thus identifying their

origins from specific chromosomes. In the example depicted, allele C is linked to a mutation responsible for autosomal dominant polycystic kidney disease (PKD). Application of this to

detect progeny carrying the disease gene is illustrated in one hypothetical pedigree.

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