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Etiology and Genomics

Page history last edited by Oaitse Kebatlege 8 years, 7 months ago

Genomics of Huntington’s Disease


This gene mutation occurs in the gene called Huntingtin (HTT) that codes for the Huntingtin protein. The mutation that occurs within this gene is a trinucleotide repeat (TNR). The location of this single gene disorder was found to be located on chromosome 4p16.3.  In a normal individual this trinucleotide repeat CAG (Cytosine, Adenine. Guanine) occurs 10 to 35 times along the DNA segment. However, an individual with Huntington disease will have trinucleotides repeat out of the normal range i.e. >36.

This gene mutation is known as trinucleotide expansion, which will result in the translation of a mutated form of the Huntingtin protein that can impair the functions of neurons of the Central Nervous system. HD is one of TNR diseases that exhibits genetic anticipation.


   Genetic anticipation in HD results in an increased trinucleotide expansion, accompanied by an increase in severity of the disease, as the genetic mutation is transmitted to offspring.

In a study by (The Huntington’s collaborative research group, 1993), a 500kb segment between chromosomal positions D4S782 and D4S780 was identified to be in association with the genetic defect. Haplotype analysis revealed that at least one third of the HD chromosomes had come from the same progenitor. Three genes were identified in the 500kb region including (ADDA) which are; the a-adducin gene, the putative novel transporter gene (ITIOC3), as well as a unique gene coding for the protein-coupled receptor kinase (IT11). These genes were identified using exon amplification methodology because it was important to know if the genes played a role in coding HD. It was then found that on the terminal of the 500kb segment, there is a IT15 gene which has a reading frame that has polymorphic (CAG) trinucleotide repeats. This segment of  nucleotide repeats is much more frequent and can be around 42 to 66 copies in HD patients whereas in normal individuals, 17 alleles have been found to contain about 11 to 34 CAG copies. Thus, repeats do not have any relationship with the age of the individual.


According to Moncke & Buchner et al. (2002), the IT15 gene on the short arm of chromosome 4 codes for the Huntingtin protein. On a defective gene in  HD, a mutation of CAG repeats is the disease causing factor located on exon 1. The CAG repeats that are mutated,  become polyQ through the process of translation. The disease is then seen when the polyQ exceeds the pathological threshold of 37 glutamines. In the pathological range, polyQ tracts and Huntingtin code for proteins that are fibrous in their morphology, the formation mechanism of which is not yet understood.                




Example of a pedigree of a family with Huntington’s disease:






There is a 50% chance of inheriting the defective HTT gene, when a single parent has the disease. The progeny that inherit this defective gene will develop the disease and can pass it on to subsequent generations and ( there is no skipped generation in the transmission of this disease) .The disease can be developed despite not having any family history, though this is rare.

Individuals with HD may exhibit CAG segment repeats in the range of  40 to over 100. Non symptomatic persons may have less than 36. Clinical evaluation and laboratory testing is needed to identify the extent of the repeats. 








Image showing what happens at different amount of CAG repeats.


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