HTT

About HTT

HTT on chromosome 4p16.3 encodes huntingtin, a large protein involved in vesicle transport, transcriptional regulation, and neuronal survival. An expansion of a CAG trinucleotide repeat in exon 1 causes Huntington disease, an autosomal dominant neurodegenerative disorder. Alleles with 40 or more repeats are fully penetrant, alleles with 36 to 39 repeats show reduced penetrance, and very large expansions are associated with the juvenile form. Longer repeats are associated with earlier onset, but repeat length does not fully determine it. The expanded polyglutamine tract makes the protein prone to aggregation, and the striatum, especially the caudate and putamen, is most affected. The disease causes chorea, cognitive decline, and psychiatric symptoms such as depression and irritability, usually beginning in mid adulthood and progressing over many years. Anticipation, the tendency of repeats to expand in successive generations, is more pronounced with paternal transmission. The gene was mapped in 1983, the first disease gene mapped using DNA markers, and identified in 1993, work aided by studies of large families near Lake Maracaibo in Venezuela. Presymptomatic testing is offered with genetic counseling. Tetrabenazine and deutetrabenazine are used to treat chorea.