19 - Trinucleotide expansions

Trinucleotide expansions

© SPMM Course Leber's hereditary optic neuropathy (LHON) is the commonest cause of blindness in young men, with bilateral loss of central vision and cardiac arrhythmias. These diseases are purely maternally inherited. Mitochondrial DNA codes for 13 proteins involved in the respiratory chain in addition to 22 tRNAs and 2 ribosomal RNAs. Many other syndromes have been described. Myopathies include chronic progressive external ophthalmoplegia (CPEO); encephalomyopathies include myoclonic epilepsy with ragged red fibres (MERRF) and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). Kearus-Sayre syndrome includes ophthalmoplegia, heart block, cerebellar ataxia, deafness and mental deficiency due to long deletions and rearrangements. Trinucleotide expansions Trinucleotides repeat disorders are a set of genetic disorders caused by trinucleotide repeats (codons – e.g. CGG, CTG, CAG, etc.) in certain genes exceeding the normal number of repeats. The mutation results in an unstable site, which is often fragile. Anticipation refers to a pattern of inheritance in which individuals in the most recent generations of an affected family develop a disease at an earlier age and with greater severity than those in previous generations. This is mostly due to the gradual expansion of trinucleotide repeat polymorphisms (this instability is called a dynamic mutation).

Fragile X genetics: This X-linked condition accounts for more cases of mental retardation in males than any condition except Down syndrome with the frequency of 1 in 4000. It can affect females but 50% less frequently than in males. A fragile site near the tip of the long arm of the X chromosome was initially suspected. Now it is known that fragile X results from the an expansion of a trinucleotide repeat (CGG) proximal to FMR1 gene. If the number of CGG repeats in this location increases beyond 52, this destabilizes this sequence allowing further expansion during spermatogenesis or oogenesis. Being born with one FMR1 allele with 200 or more repeats results in lower IQ in most men and ~ 60% of women. The phenomenon of anticipation is seen. Unlike men, heterozygous women usually have the other X chromosome that can compensate to some extent; thus they show no physical signs other than early menopause, mild learning difficulties and rarely frank retardation. Affected males suffer from enlarged testes, prominent ear lobes and a protracting jaw, a high-pitched voice, and mental retardation. Some men carry an increased number of CGG repeats in the FMR1 locus but do not show a full-blown clinical phenotype; these individuals are called premutation carriers. Though premutant carriers were long thought to be free from clinical features, it is now known that they are at increased risk for developing intention tremor and ataxia especially after middle age. Women who are premutation carriers (55–200 CGG repeats) are at increased risk of premature ovarian failure and/or mild cognitive or behavioral abnormalities. The fragile site at first exon of FMR1 is called FRAXA, a second site at Xq28 called FRAXE Frag(g)ile X syndrome Frag(g)ile X syndrome •cGG Friedreich AtaxiA Friedreich AtaxiA •gAA Huntington ChoreA Huntington ChoreA •CAg MyoTonic dysTrophy MyoTonic dysTrophy •cTg

© SPMM Course is also linked to mental retardation. FRAXF is the third fragile site sensitive to folate, but not linked to MR. Similar to Myotonic Dystrophy (but in contrast to Huntington’s), anticipation rates are higher in maternal than paternal inheritance. This is because further trinucleotide expansion occurs during oogenesis rather than spermatogenesis. Huntington’s genetics: Huntington's disease is inherited in an autosomal dominant manner with full penetrance and a prevalence rate of about 5 per 100,000. The gene responsible is an expanded and unstable CAG trinucleotide repeat on the short arm of chromosome 4 - 4p16.3. This results in translation of an extended glutamine sequence in huntingtin, the protein product of the gene. Huntingtin is expressed throughout the body. Its function is unclear. Though slightly unusual for a genetic disease; the onset is usually between 30 and 50 years of age. Most adult-onset HD cases have CAG expansions of 40-55 repeats while greater expansions (>70 repeats) are seen in childhood-onset HD. The phenomenon of anticipation is seen here too. But unlike other X-linked disorders (see myotonic dystrophy below), inheritance of HD from the father is associated with the greater repeat expansion and earlier age of onset. Nearly one-third of father-to-offspring cases show an expansion resulting in juvenile-onset HD. Characteristic protein deposits form nuclear inclusions in neurons of HD patients. Myotonic dystrophy is another neurological disease with trinucleotide repeat expansion. Here CTG repeats are expanded. The anticipation resulting from trinucleotide instability is higher if the inherited expansion comes from the mother than the father in MD. This is because oogenesis, due to its inherently long dormancy compared to spermatogenesis, results in much higher instability. As a result anticipation is more prominent in maternal transmissions. Genomic imprinting Though no structural differences exist between maternal and paternally inherited chromosomes in humans, there are some subtle functional differences, which are increasingly being appreciated. For example, a deletion of part of the long arm of chromosome 15 (15q11-q13) will give rise to the Prader-Willi syndrome (PWS) if it is paternally inherited. A deletion of a similar region of the chromosome gives rise to Angelman's syndrome (AS) if it is maternally inherited. This may be due to differential regional expression of the chromosomes. Maternal chromosome 15q11-13 is expressed in the brain and hypothalamus, leading to neuronal damage in its absence. This phenomenon is called genomic imprinting. It is thought to be due to DNA methylation effects.

In genomic imprinting, the disease phenotype expressed depends on whether the allele is of maternal or paternal lineage. This parent-of-origin phenomenon is an important exception to the Mendelian inheritance patterns. Approximately 70% of patients with Prader Willi syndrome have a deletion in their paternally derived 15q11-q13. Maternal uniparental disomy (inheriting both copies from mother when embryo is formed) occurs in most of the remaining patients (25%). Most patients with Angelman’s syndrome have a deletion in their maternally derived 15q11-q13. Paternal uniparental disomy occurs in about 4% of Angelman’s syndrome.