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MRCPath Part 1 18/09/2008 Stephanie Batey

Describe how the identification of triplet repeat mutations has improved our understanding of the genetics and clinical expression of some of the inherited neurological disorders. MRCPath Part 1 18/09/2008 Stephanie Batey. Introduction.

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MRCPath Part 1 18/09/2008 Stephanie Batey

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  1. Describe how the identification of triplet repeat mutations has improved our understanding of the genetics and clinical expression of some of the inherited neurological disorders. MRCPath Part 1 18/09/2008 Stephanie Batey

  2. Introduction • Trinucleotide expansion represents a novel type of mutation. • Fragile X and SBMA found to be caused by triplet repeat expansion in 1991. • At least 17 inherited human neurological disorders now known to be associated with triplet repeat expansion. • Trinucleotide repeat expansion disorders are categorised into two subclasses: Class I CAG repeat expansions in coding regions of genes Expansions generally much smaller in size and variation. Associated with neuronal loss in brain, brainstem and spinal cord. Mainly dominant inheritance with the exception of SBMA. Class II Expansions in non-coding regions of genes Typically characterised by large and variable repeat expansions. Multiple tissue dysfunction or degeneration. Trinucleotide repeat sequences vary

  3. Common features of trinucleotide repeat expansions (TRE). • Expanded trinucleotide repeats are inherently unstable Dynamic mutations - tendency towards further lengthening. • Dynamic expansions result in variability in the age of onset, degree of severity and clinical presentation of TRE disorders. • Repeat expansions demonstrate extreme instability in both the germline and somatic tissue: Germline/ meiotic instability Significant intergenerational instability has been observed in TREs. Provides a molecular explanation for anticipation and non-Mendelian inheritance patterns. Somatic/ mitotic instability Expanded alleles often show size variation within the tissues of an affected individual accounting for the symptom variability associated with TREs. • Increased repeat lengths generally correlate with an earlier age of onset and more severe disease phenotype.

  4. Cis- and trans-acting factors influence the instability of expanded alleles • Founder effects are a common feature of dynamic mutation. • Some of the known TRE disorders are multisystemic, but they all exert major effects on the nervous system suggesting that neurons are particularly susceptible to damage by these mutations.

  5. Germinal/ Meiotic instability • Most trinucleotide repeats are highly polymorphic in the normal range and the expanded disease range. • Stable transmission of normal sized alleles form parent to child. • In patients, the repeat number exceeds a threshold at which instability begins to occur. • Repeat size ranges have been determined for each of the TRE diseases. • The correlation between repeat length and disease severity and the tendency of expanded trinucleotide repeats to undergo further expansion when transmitted from parent to offspring accounts for the phenomenon of anticipation. • Repeat size distributions and intergenerational length changes differ between CAG expansion disorders and untranslated TRE disorders with respect to repeat instability.

  6. Factors which influence repeat instability include: • repeat length • location of the repeat in a gene • sex of transmitting parent • repeat composition • flanking DNA sequence and other cis-acting sequences. 1) Repeat length • Trinucleotide repeat instability is influenced by the size of the parental repeat – longer repeats are more likely to expand. • Arrays typically <30 repeats in general population Disease-associated alleles are usually > 40 repeats in patients • Correlation between increasing repeat size and disease severity. • Non-coding TRE disorders and CAG expansion disorders differ in the size of the expanded allele and the instability thresholds.

  7. 2) Repeat location • Downstream pathology in TREs is mediated by a variety of different complex molecular pathways. • Sizes of normal and disease alleles are notably different among the different disorders. • Subtle differences among the normal and abnormal CAG repeat ranges and distributions for the different diseases

  8. 3) Parental bias • Sex differences in triplet repeat instability are related to parental biases in the transmission of disease alleles. • Parental bias has been described in both classes of TRE disorders and holds clinical importance. • Examples: Fragile X: premutation alleles show significant instability in the female germline. Congenital DM: usually only transmitted by affected mothers. • Anticipation associated with an expansion bias on paternal transmission for the majority of TREs, particularly the PolyQ diseases. • Sex and disease- dependent meiotic instability correlates with the observation of a paternal bias among juvenile onset cases for HD, SCA1 and DRPLA.

  9. 4) Cis-acting elements • Examples of cis-acting factors include copy number and composition of the repeat. High copy number and perfect repeat more unstable (Richards, 2001). • Sequence interruptions important in determining stability. • First studied for SCA1 alleles – loss of CTA interruptions is a prerequisite for CAG repeat instability at the SCA1 locus. • Adjacent sequence variation may contribute to the instability of the CAG repeat eg HD

  10. Nonpenetrance, mutability and intermediate alleles • The existence of de novo mutations suggests some repeat sequences acquire the abnormal property of meiotic instability before acquiring the ability to cause disease. • Identification of incomplete penetrance of disease phenotypes for repeat lengths at the low end of the abnormal range. • Premutation alleles do not themselves cause symptoms but can give rise to de novo mutations probably due to meiotic instability combined with proximity to disease threshold. • Reduced penetrance/ intermediate used to describe alleles which can cause symptoms but do not always do so within a normal life expectancy. • Explanation for late onset of symptoms.

  11. Somatic instability • Expanded triplet repeats can show length variation in different tissues. • Presence of different sized repeats in different tissues from the same individual = somatic mosaicism/ mitotic instability. • Assumed to result from cellular proliferation during development and differentiation. • Thought to contribute to the progressive nature and tissue-specificity of the symptoms. • Initially revealed by the diffuse heterogeneous smears on Southern blot analysis. • Somatic mosaicism of disease-associated alleles tends to be age-dependent, expansion-biased and highly tissue-specific. • Documented in all the expanded CAG-CTG repeat disorders. Somatic repeat variability has also been described for DM2, SCA10, FRAXA and FRDA.

  12. Somatic instability (2) • Untranslated repeat disorders show large degrees of somatic mosaicism. Correlates with the size of repeat expansion. • CAG diseases show lesser degrees of somatic mosaicism. Correlates with the amount of meiotic instability for the corresponding disease eg HD • CAG repeat diseases tend to have a greater repeat length variability within the central nervous system. • DM displays high levels of somatic instability and considerable inter-tissue differences. Expansion size in muscle is consistently larger than in circulating leukocytes. • Evidence to show that somatic instability in FRDA occurs mostly after early embryonic development and progresses throughout life: indicates a role of postnatal somatic instability in disease pathogenesis.

  13. References • Siyanova & Mirkin (2000) Molecular Biology 35(2):168-182 • Richards, R.I. (2001) Human Molecular Genetics 10(20): 3187-3194 • Monckton & Caskey (1995) Circulation 91:513-520 • Gomes-Pereira & Monckton (2006) Mutation Research • Sinden et al (2002) J. Biosci. 27(1) 53-65 • Timchenko & Caskey (1999) CMLS 55: 1432-1447 • Nance (1997) Brain Pathology 7:881-900 • Fortune et al (2000) Human Molecular Genetics 9(3): 439-445 • La Spada (1997) Brain pathology 7: 943-963 • La Spada et al (1994) Ann Neurol 36(8): 814-822

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