Chapter 062. Principles of Human Genetics (Part 24)

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Nucleotide Repeat Expansion Disorders Several 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) Nucleotide Repeat Expansion Disorders Several 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 generation to the next, disease manifestations may worsen or be observed at an earlier age; this phenomenon is referred to as anticipation. In Huntington disease, for example, there is a
correlation between age of onset and length of the triplet codon expansion (Chap. 360). Anticipation has also been documented in other diseases caused by dynamic mutations in trinucleotide repeats (Table 62-6). The repeat number may also vary in a tissue-specific manner. In myotonic dystrophy, the CTG repeat may be tenfold greater 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 Andro chromosomal 1-q12 G 34/40–62 gen receptor spinobulbar muscular atrophy (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, Myot a myotonica 3.2-q13.3 G 30/200–1000 variable onin protein (DM) penetrance kinase Huntingt 4p16 CA 6– AD Hunti on disease (HD) .3 G 34/37–180 ngtin Spinocere 6p21 CA 6– AD Ataxi bellar ataxia .3-21.2 G 39/40–88 n1 type 1 (SCA1) Spinocere 12q2 CA 15– AD Ataxi bellar ataxia 4.1 G 31/34–400 n2 type 2 (SCA2)
Spinocere 14q2 CA 13– AD Ataxi bellar ataxia 1 G 36/55–86 n3 type 3 (SCA3); Machado Joseph disease (MD) Spinocere 19p1 CA 4– AD Alpha bellar 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 Ataxi bellar ataxia .1-p12 G 19/37 to n7 type 7 (SCA7) >300 Spinocere 5q31 CA 6– AD Protei bellar ataxia G 26/66–78 n type 12 phosphatase (SCA12) 2A
Dentorub 12p CA 7– AD Atrop ral G 23/49–75 hin 1 pallidoluysiane atrophy (DRPLA) Friedreic 9q13 GA 7– AR Fratax h ataxia -21 A 22/200–900 in (FRDA1)