Chapter 062. Principles of Human Genetics (Part 24)

Nucleotide Repeat Expansion DisordersSeveral diseases are associated with an increase in the number of nucleotide repeats above a certain threshold (Table 62-6). The repeats are sometimes located within the coding region of the genes, as in Huntington disease or the X-linked form of spinal and bulbar muscular atrophy (SBMA, Kennedy syndrome). In other instances, the repeats probably alter gene regulatory sequences. If an expansion is present, the DNA fragment is unstable and tends to expand further during cell division. The length of the nucleotide repeat often correlates with the severity of the disease. When repeat length increases from one...
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Chapter 062. Principles of Human Genetics (Part 24) Chapter 062. Principles of Human Genetics (Part 24) Nucleotide Repeat Expansion Disorders Several diseases are associated with an increase in the number of nucleotiderepeats above a certain threshold (Table 62-6). The repeats are sometimes locatedwithin the coding region of the genes, as in Huntington disease or the X-linkedform of spinal and bulbar muscular atrophy (SBMA, Kennedy syndrome). In otherinstances, the repeats probably alter gene regulatory sequences. If an expansion ispresent, the DNA fragment is unstable and tends to expand further during celldivision. The length of the nucleotide repeat often correlates with the severity ofthe disease. When repeat length increases from one generation to the next, diseasemanifestations may worsen or be observed at an earlier age; this phenomenon isreferred to as anticipation. In Huntington disease, for example, there is acorrelation between age of onset and length of the triplet codon expansion (Chap.360). Anticipation has also been documented in other diseases caused by dynamicmutations in trinucleotide repeats (Table 62-6). The repeat number may also varyin a tissue-specific manner. In myotonic dystrophy, the CTG repeat may be tenfoldgreater in muscle tissue than in lymphocytes (Chap. 382). Table 62-6 Selected Trinucleotide Repeat Disorders Disease Loc Re Triple Inherit Gene us peat t Length ance Product (Normal/Dis ease) X- Xq1 CA 11– XR Androchromosomal 1-q12 G 34/40–62 gen receptorspinobulbarmuscularatrophy (SBMA) Fragile Xq2 CG 6– XR FMR-X-syndrome 7.3 G 50/200–300 1 protein(FRAXA) Fragile Xq2 GC 6– XR FMR-X-syndrome 8 C 25/>200 2 protein(FRAXE) Dystrophi 19q1 CT 5– AD, Myota myotonica 3.2-q13.3 G 30/200–1000 variable onin protein(DM) penetrance kinase Huntingt 4p16 CA 6– AD Huntion disease (HD) .3 G 34/37–180 ngtin Spinocere 6p21 CA 6– AD Ataxibellar ataxia .3-21.2 G 39/40–88 n1type 1 (SCA1) Spinocere 12q2 CA 15– AD Ataxibellar ataxia 4.1 G 31/34–400 n2type 2 (SCA2) Spinocere 14q2 CA 13– AD Ataxibellar ataxia 1 G 36/55–86 n3type 3 (SCA3);Machado Josephdisease (MD) Spinocere 19p1 CA 4– AD Alphabellar ataxia 3.1-13.2 G 16/20–33 1A voltage-type 6 (SCA6, dependent L-CACNAIA) type calcium channel Spinocere 3p21 CA 4– AD Ataxibellar ataxia .1-p12 G 19/37 to n7type 7 (SCA7) >300 Spinocere 5q31 CA 6– AD Proteibellar ataxia G 26/66–78 ntype 12 phosphatase(SCA12) 2A Dentorub 12p CA 7– AD Atropral G 23/49–75 hin 1pallidoluysianeatrophy(DRPLA) Friedreic 9q13 GA 7– AR Frataxh ataxia -21 A 22/200–900 in(FRDA1)