Huntingtin (Htt) is the protein coded by the HD gene (which itself is sometimes called the Huntingtin gene). It is variable in its structure. There are many polymorphisms of the HD gene which can lead to variable numbers of glutamine residues present. In its wild-type (normal) form, it contains 6-34 glutamine residues. In individuals affected by Huntington's Disease, an autosomal dominant genetic disorder, it contains between 35-155 glutamine residues. Huntingtin has a predicted mass of ~350kDa, however, this varies and is largely dependent on the number of glutamine residues in the protein. Normal huntingtin is generally accepted to be 3144 amino acids in size.
The function of Huntingtin is unclear. It is essential for development and absence of huntingtin is lethal in mice. The protein has no sequence homology with other proteins and is highly expressed in neurons and testes in humans and rodents. It has however been experimentally demonstrated that Huntingtin acts as a transcription factor in upregulating the expression of Brain Derived Neurotrophic Factor (BDNF). In the deficient protein, there is suppression of this transcription regulatory function of Huntingtin and hence underexpression of BDNF.
Huntingtin has also been found to interact with a number of proteins. One such protein is the Huntingtin Interacting Protein I (HIP-I/Hip-1). Unfortunately the actions mediated via these interactions of huntingtin with the complementary interacting proteins are not fully understood.
Abnormal huntingtin (mHtt)
The key sequence which is found in Huntington's disease (HD) is a stretch of glutamine residues beginning at the 18th amino acid. In unaffected individuals, this stretch contains between 9 and 35 glutamine residues with no adverse effects. However, individuals with HD have an expansion up to around 100 glutamines in this region of the gene. A greater number of residues is associated with earlier onset of the disease.
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