Everyone has two copies of the<unk>  gene (HTT), which codes for the<unk>  protein (Htt). HTT is also called the<unk>  gene, and the IT15 gene, (interesting transcript 15). Part of this gene is a repeated section called a trinucleotide repeat expansion – a short repeat, which varies in length between individuals, and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant<unk>  protein (mHtt). The differing functions of these proteins are the cause of pathological changes, which in turn cause the disease symptoms. The<unk>  mutation is genetically dominant and almost fully penetrant; mutation of either of a person's HTT alleles causes the disease. It is not inherited according to sex, but by the length of the repeated section of the gene, hence its severity can be influenced by the sex of the affected parent. Genetic mutation<unk>  is one of several trinucleotide repeat disorders that are caused by the length of a repeated section of a gene exceeding a normal range. The HTT gene is located on the short arm of chromosome 4 at 4p16.3. HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat. CAG is the three-letter genetic code (codon) for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the polyQ region. Graphic showing at top normal range of repeats, and disease-causing range of repeats. +Classification of trinucleotide repeats, and resulting disease status, depending on the number of CAG repeats Repeat count Classification Disease status Risk to offspring <27 Normal Will not be affected None 27–35 Intermediate Will not be affected Elevated, but <50% 36–39 Reduced Penetrance May or may not be affected 50% 40+ Full penetrance Will be affected 50% Generally, people have fewer than 36 repeated glutamines in the polyQ region, which results in the production of the cytoplasmic protein<unk> . However, a sequence of 36 or more glutamines results in the production of a protein with different characteristics. This altered form, called mutant<unk>  (mHtt), increases the decay rate of certain types of neurons. Regions of the brain have differing amounts and reliance on these types of neurons and are affected accordingly. Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to the environment and other genes that modify the mechanism of<unk> . About 36 to 39 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases, the onset may be so late that symptoms are never noticed. With very large repeat counts (more than 60),<unk>  onset can occur below the age of 20, known as juvenile<unk> . Juvenile<unk>  is typically of the Westphal variant that is characterised by slowness of movement, rigidity, and tremors. This accounts for about 7% of<unk>  carriers. Inheritance<unk>  is inherited in an autosomal dominant fashion. The probability of each offspring inheriting an affected gene is 50%. Inheritance is independent of sex, and the phenotype does not skip generations.<unk>  has autosomal dominant inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant allele) from an affected parent. Since the penetrance of the mutation is very high, those who have a mutated copy of the gene will have the disease. In this type of inheritance pattern, each offspring of an affected individual has a 50% risk of inheriting the mutant allele, so are affected with the disorder (see figure). This probability is sex-independent. Trinucleotide CAG repeats numbering over 28 are unstable during replication, and this instability increases with the number of repeats present. This usually leads to new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the trinucleotide repeat. This causes the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28–35), or "reduced penetrance" (36–40), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant<unk> . The earlier age of onset and greater severity of disease in successive generations due to increases in the number of repeats is known as genetic anticipation. Instability is greater in spermatogenesis than oogenesis; maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length. Rarely is<unk>  caused by a new mutation, where neither parent has over 36 CAG repeats. In the rare situations where both parents have an expanded<unk>  gene, the risk increases to 75%, and when either parent has two expanded copies, the risk is 100% (all children will be affected). Individuals with both genes affected are rare. For some time,<unk>  was thought to be the only disease for which possession of a second mutated gene did not affect symptoms and progression, but it has since been found that it can affect the phenotype and the rate of progression.
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