MICROSATELLITES AND DISEASE
Introduction:
Microsatellite sequences are repeating DNA sequences. For example, in one part of chromosome number 4, CAG nucleotides are repeated many times over. They look like this: CAGCAGCAGCAG...... If the trinucleotides are repeated too many times this would cause the person to get Huntington's disease in adult life. Other diseases that involve repeats of three nucleotides are also known to cause neurological diseases (see below). At this time 14 neurological disor ders have been shown to result from the expansion of trinucleotide repeats, establishing an expanding class of diseases. Trinucleotide repeat diseases can be categorised into two subclasses based on the location of the trinucleotide repeats: diseases involving noncoding repeats (untranslated sequences) and diseases involving coding sequences (exonic). In general trinucleotide repeat disorders are either dominantly inherited or X-linked, the one exception being Friedrich's ataxia, which is autosomal recessive (Goldstein and Schlotterer, 1999; Cummings and Zoghbi, 2000).
Not all diseases are caused by a mistake in one gene. Sometimes many genes may be involved in a disease, for example, in schizophrenia. For these diseases microsatellite sequences have been used as a marker for locating the diseased region of the chromosome. This method is called positional cloning. Microsatellite markers close to the disease gene correlate with the heredity of the disease, and by analysis of these markers within families scientists can predict how the disease will be inherited (Risch, 2000).
EXAMPLES OF DISEASES INVOLVING TRINUCLEOTIDE REPEATS
Huntington's disease
Symptoms: Late onset dementia and loss of motor control, resulting in full-blown chorea after 10-20 years. Motor disorder is often preceded or accompanied by memory deficits, cognitive decline or changes in personality. Juvenile onset is rare and patients show rigidity, bradykinesia, epilepsy, severe dementia and an accelerated disease course.
Involvement of microsatellites: CAG coding repeat in the first exon of the HD gene. Normal gene contains between 6 and 35 repeats and the affected gene from 36 to 121 repeats. Adult onset typically occurs when the repeat contains 40 - 50 units, whereas alleles containing more than 70 repeats typically result in the more severe juvenile form. The microsatellite adds a string of glutamine amino acids to the huntingtin protein
Chromosome location: #4
Internet link to real story: http://www.hdac.org/
Fragile X
Symptoms: Mental retardation, long and prominent ears and jaws, high-pitched speech, hyperactivity, poor eye contact, and stereotypic hand movements (e.g. hand-flapping and hand-biting). 1 in 4000 males are affected, and fewer females are affected, depending on the ratio of cells with normal X chromosome active to abnormal X active.
Involvement of microsatellites: The repeat is CGG in a non-coding region of the FMR2 gene, and normal is 6 - 53 repeats. The disease occurs if the repeat is between 60 - 200.
Chromosome location: X
Link to real story: http://www.conquerfragilex.org
Myotonic dystrophy
Symptoms: Congenital DM is the most severe form of this disease involving hypotonia, respiratory distress at birth and developmental abnormalities. Adult onset includes variable loss of mental function, myotonia, muscle weakness and progressive muscle wasting. Other features may include facial dysmorphology, presenile cataracts, testicular atrophy, premature balding in males, kidney failure, hyperinsulin secretion and cardiac conduction abnormalities.
Involvement of microsatellites: CTG repeats in a non-coding region of the DMPK gene. Normal is between 5 and 37, the disease may involve from 50 - 1000s of repeats.
Chromosome location: #19
Spinalbulbar muscular atrophy
Symptoms: Neurological degeneration leading to difficulties in speech, articulation and swallowing, muscle weakness and atrophy. Signs of mild androgen insensitivity are typically seen at adolescence.
Involvement of microsatellites: CAG repeat in first coding exon of the androgen receptor (AR) gene. Between 9 and 36 repeats is normal, and people with 38-62 repeats develop the disease.
Chromosome location: X, recessive.
Friedrich's ataxia
Symptoms: Ataxia, diminished tendon reflexes, loss of position and vibratory senses, dysarthria (slurred speech), cardiomyopathy, diabetes mellitus, optical atrophy, scoliosis and skeletal abnormalities. Age of onset is typically early childhood.
Involvement of microsatellites: GAA repeat in non-coding region of gene X25. Normal gene contains between 7 and 34 repeats. The disease gene has 34 to 80 repeats.
Chromosome location: #9, recessive
More information: http://www.ich.ucl.ac.uk/cmgs/fried.htm
EXAMPLES OF DISEASES FOUND BY POSITIONAL CLONING
Schizophrenia and Bipolar Disorder
Symptoms: Schizophrenia is characterized by auditory and visual hallucinations and delusions; symptoms of bipolar disorder involve severe mood swings, between mania and depression.
Involvement of microsatellites: Using 388 microsatellite markers within 8 families the researchers (Bailer et al., 2002) found a susceptibility locus for both schizophrenia and bipolar disorder on chromosome 3.
Chromosome location: #3
More information: http://www.psychiatry24x7.com
Congenital generalized hypertrichosis
Symptoms: Rare hair growth disorder, characterized by excessive hair growth on the face and upper body; sometimes called "werewolf" syndrome.
Involvement of microsatellites: Using hypervariable microsatellite markers the researchers (Figurea et al., 1995) localized the gene to a part of the X chromosome.
Chromosome location: X, dominant.
More information: http://www.bbc.co.uk/science/horizon/hopefulmonsters.shtml
http://www.circusfolks.com/apub/mainhtml
Asthma and Bronchial Hyperresponsiveness
Symptoms: Common respiratory disorder characterized by recurrent episodes of coughing, wheezing and breathlessness.
Involvement of microsatellites: A putative asthma susceptibility gene was identified on the ADAM33 region of chromosome 20 (Van Eerdewgh et al., 2002).
Chromosome location: #20
Detecting Cancer
The rate of microsatellite expansion (that is, increase in the number of repeats) or contraction (decrease in number of repeats) in cells is increased in some types of cancers, due to defects in enzymes that correct copying mistakes in DNA. Early clinical detection of some types of colon and bladder cancers using changes in microsatellite repeats have been successful (Yonekura et al., 2002; Moxon and Willis, 1999).
References
Moxon, E. R. and Wills, C., 1999. DNA microsatellites: agents of evolution. Scientific American, Jan 1999, 94-99.
Risch, N., 2000. Searching for genetic determinants in the new millennium. Nature 405, 847-856
Bailer, U. et al., 2002. Genome scan for susceptibility loci for schizophrenia and bipolar disorder. Biol. Psychiatry, 52(1), 40-52.
Cummings, C.J. and Zoghbi, H.Y., 2000. Trinucleotide repeats: mechanism and pathophysiology. Ann. Rev. Genomics Hum. Genet. 1, 281-328.
Van Eerdewegh, P. et al., 2002. Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness. Nature 418, 426 -430.
Figuera, L.E. et al., 1995. Mapping of the congenital generalized hypertrichosis locus to chromosome Xq24-Xq27.1. Nature Genetics 10(2), 202-7.
Hall, B.K., 1995. Atavisms and atavistic mutation. Nature Genetics 10(2), 126-7.
Goldstein, David B. and Schlotterer, C. Microsatellites: Evolution and Applications. Oxford University Press, 1999, NY.