Triplet repeats

Some very unusual nucleotide bonding has been discovered in so-called triplet repeat sequences [23], Two neighboring bases in one strand complex with a single base of the opposite strand in a complex, which is called triad DNA. This type of bonding requires three bases, but unlike triplexes the three bases are within only two DNA strands. 

Davies SW, Beardsall K, Turmaine M, DiFiglia M, Aronin N, Bates GP. Are neuronal intranuclear inclusions the common neuropathology of triplet-repeat disorders with polyglutamine-repeat expansions Lancet 1998 351 131-133. 

Becher MW, Kotzuk JA, Sharp AH, Davies SW, Bates GP, Price DL, Ross CA. Intranuclear neuronal inclusions in Huntington s disease and dentatorubral and pallidoluysian atrophy correlation between the density of inclusions and IT15 CAG triplet repeat length. Neurobiol Dis 1998 4 387-397. 

Lieberman AP, Fischbeck KH. Triplet repeat expansion in neuromuscular disease. Muscle Nerve 2000 23[6] 843—850. 

Friedreich s ataxia is caused by an intronic triplet repeat expansion. Friedreich s ataxia is an autosomal recessive disorder characterized by progressive ataxia, nystagmus, distal sensory polyneuropathy and corticospinal tract degeneration. It is caused by an unstable expanded GAA repeat in intron 1 of the frataxin gene on chromosome 9ql3. This diminishes expression of frataxin, a mitochondrial iron-storage protein that participates in free radical metabolism [71]. 

Triplet repeat disorders are characterized by 3-base-pair nucleotide repeats that lie in either coding or noncoding regions and give rise to a multitude of different... 

The mutated gene products in all these cases exhibit toxic gain of function. See Triplet Repeat Disorders in Ch. 39 and Huntington s Disease in Chs 39 and 46 for discussions of genetic pathology. 

Triplet repeat expansion Expansions in coding regions cause protein product to be longer than normal and unstable. Disease often shows anticipation in pedigree. 

Answer C, PCR primers flanking the mutation, as well as Southern blottii would be needed to detect the extent of the triplet repeat expansion. 

Many genes contain triplet repeats in either coding or noncoding regions that is, a... 

This is normal and usually causes no problem. However, in some cases, the triplet repeat segment of the gene is expanded. This growth may increase in successive generations of families. If the triplet repeat number becomes too great, disease can result. Here are two specific examples, Huntington s disease and Fragile X syndrome. 

Every third amino acid in most collagen chains is glycine, in triplet repeats of the sequence Gly-Pro-X and Gly-X-hydroxyproline, where X = any amino acid. 

In fragile X syndrome, triplet repeat expansions are responsible for the majority of cases. It should be noted, however, that any mutation that disrupts the functional activity of the FMRl protein could lead to a similar phenotype. This was in fact established when a patient with severe fragile X syndrome was found who did not have a triplet repeat expansion. Rather, this patient had a point mutation that changed a highly conserved amino acid within the RNA-binding domain of the FMRl protein (De Boulle et al., 1993 Siomi et al., 1994 Musco et... 

Margolis, R. and Ross, C. (1999) Triplet repeat disorders./Am Acad Child Adolesc Psychiatry 38 1598-1600. 

Sidransky, E., Burgess, C., Ikeuchi, T., Lindblad, K., Long, R.T., Philibert, R.A., Rapoport, J., Schalling, M., Tsuji, S., and Ginns, E.I. (1998) A triplet repeat on 17q accounts for most expansions detected by the repeat-expansion-detection technique. Am ] Hum Genet 62 1548-1551. 

Campuzano V, Montermini L, Molto MD, Pianese L, Cossee M, Cavalcanti F, Monros E, Rodius F, Duclos F, Monticelli A, Zara F, Canizares J, Koutnikova H, Bidichandani SI, Gellera C, Brice A, Trouillas P, DeMichele G, Filla A, DeFrutos R, Palau F, Patel PI, DiDonato S, Mandel JL, Cocozza S, Koenig M, Pandolfo M (1996) Friedreich s ataxia autosomal recessive disease caused by an intronic GAA triplet repeat expansion. Science 271 1423-1427... 

Role of tandem triplet repeats in mRNA causing Huntington disease and other gene expansion diseases. 

Some Human Triplet Repeat and Related Diseases3... 

Twelve or more additional triplet repeat diseases, many with neurological symptoms, have been identified (Table 26-4).405 407a These involve other trinucleotide repeats 5 -(GCG) , 5 -(CTG) , 5 -(GAA) , and 5 -(CAG) . In synpolydactyly, an inherited developmental defect causing malformation of hands and feet, an expansion of a GCG trinucleotide occurs within the gene HoxD 13. This results in incorporation of a polyalanine tract near the N terminus of the protein.408 Myotonic dystrophy DM1 (Box 19-A) results from expansion of CTG to 6 kbp or more within the untranslated 3 region of a gene for cAMP-dependent protein kinase.405 The mRNA transcripts accumulate... 

Figure 1-5. Diagram of the fragile X mental retardation (FAIR ) gene with restriction map and FMR1 probes used for diagnostic Southern blots. The circle indicates the CpG island, and the box represents the first exon. The dark region shows the location of triplet repeats.

This microsatellite repeat is polymorphic in normal humans, ranging from 6 to 52 repeats, with a mean of 30. In affected patients with fragile X syndrome, however, this repeat contains many times the normal number of triplet repeats between 230 and several thousand... 

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