Huntington's Disease Genetics: CAG Mutation and Inheritance

Introduction to Huntington's Disease and Chromosomal Analysis

Huntington's disease, also known as HD [MIM 143100], is a dominantly inherited, gradually progressive neurodegenerative disorder. It is caused by a mutation that leads to the expansion of a polymorphic CAG trinucleotide tract in the HTT gene. Normally, the size of the CAG repeat among ordinary individuals should be between 17 and 20 repeats. In HD patients, one or two duplicate genes have an expanded CAG tract of at least 36 repeats (Kremer et al., 1994). The polymorphic trinucleotide tract size can be uneven and is more likely to expand, particularly when transmitted through a male germline. Initially, the new mutation rate for Huntington's disease was estimated to be extremely low, and the illness was thought to affect only families with a known history of HD. Current estimates have discovered that the expansion of CAG into the disease range has become more common than previously predicted. The new mutation rate may be at least 10% (Warby et al., 2009).

Many factors are believed to cause CAG instability, including CAG tract size, interruptions of the CAG tract, the age and sex of the transmitting parent, environmental factors, genetic trans-factors, and cis-elements. Although a larger CAG tract and transmission through a male germline are clearly associated with high CAG instability, trans-factors such as DNA repair machinery are also considered major contributing factors. For example, CAG instability in transgenic HD mice was reduced after crossing with mice lacking MSH2 (MIM 609309) — a mismatch repair enzyme — or OGG1 (MIM 601982), a base excision repair enzyme. Although cis-elements are believed to modify CAG instability in various genes, prior evidence indicates that cis-elements play no role in CAG instability in HTT, the HD gene (Warby et al., 2009).

Many studies have examined the origins of HD by constructing haplotypes for the HTT region in specific population groups. This research has been conducted using small sets of allelic markers, because beyond the CAG repeat, few HTT polymorphisms had been characterized previously. Most studies identified positive associations between disease chromosomes and specific markers, concluding that HD mutations share a common descent, though not necessarily from a single founder (Warby et al., 2009).

Causes of Huntington's Disease

HD is a dominantly hereditary autosomal disease caused by a long CAG repeat located on the short arm of chromosome 4p16.3 within the huntingtin gene. This gene encodes the huntingtin protein and contains a CAG tract in exon 1. In the wild-type allele, the CAG repeat encodes a polyglutamine stretch of between 6 and 16 residues in the protein. The disease is associated with at least 36 repeats. Definite clinical presentation occurs when repeats exceed 40. A range of 36–39 repeats causes incomplete penetrance or late onset of Huntington's disease. At 29–35 repeats, intermediate alleles are unstable and are likely to expand during reproduction. Gene duplication can cause errors, and in most cases elongation — rather than shortening — occurs. This phenomenon occurs predominantly during male reproduction (Roos, 2010).

The lifespan of a Huntington's disease patient can be divided into three stages: at-risk, Stage A (preclinical), and Stage B (clinical). The first phase, at-risk, ends once it is established whether the patient carries the expanded CAG repeat on chromosome 4. If the patient carries the gene, they will proceed through Stages A and B (Roos, 2010).

Inheritance Pattern, Genomic Imprinting, and Clinical Considerations

The interaction between symptomatology (chorea or rigidity) in HD and age of onset was studied using data gathered from the Huntington's Disease Victims and Families Research Roster. The research demonstrated that age of onset varies among families and between maternal and paternal transmission. It was also found that rigidity is specifically associated with very young onset age, paternal transmission, young parental onset age, and marked anticipation. It is suggested that age of onset is dependent on the methylation state of the disease locus, which differs among familial lineages. This is caused by genomic imprinting, which depends on parental transmission. Early familial onset age and male parental imprinting interact and occasionally produce a pronounced change in gene expression, resulting in the rigid or early-onset variant (Ridley, Frith, Farrer, & Conneally, 1991).

There have been suggestions that differences in genomic methylation could account for the variations in onset age observed in HD cases. The parent from whom the patient inherited the HD allele determines this variation, and genomic imprinting differences may also be responsible for differences in symptomatology. The later HD onset age observed in offspring of affected mothers, compared to offspring of affected fathers, has been associated with a protective maternal factor. Although this factor has been proposed to reside in the mother's mitochondrial DNA, maternal genomic imprinting may also play a role (Ridley, Frith, Farrer, & Conneally, 1991).

Research has consistently shown that individuals who choose to undergo genetic testing for HD are psychologically selected for a positive response to the result. Those who reported being potentially suicidal or anticipated depression in the event of a positive result were significantly less likely to consent to testing than those who did not anticipate such responses. The primary reasons individuals chose not to test included the psychological and emotional impact of a positive result — such as fear of losing hope — as well as increased risk for their children if they were found to be carriers, the absence of a curative treatment, and the potential loss of health insurance. Individuals with limited ego strength may have derived significant benefit from the extensive psychological support offered through pre- and post-test counseling programs (Meiser & Dunn, 2001).