HTT gene — Three Level Genetics

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HTT

The HTT gene carries a stretch of DNA where the three letters CAG repeat over and over. This codes for a run of one amino acid (glutamine) inside the huntingtin protein. When the repeat expands to 36 or more copies, the protein misfolds and slowly damages brain cells, causing Huntington's disease. It is inherited in an autosomal dominant pattern, so a single expanded copy is enough, and each child of an affected parent has a 50% chance of inheriting it.

CAG repeatAutosomal dominantNeurodegeneration

Gene function

HTT encodes a large protein called huntingtin, which is found in cells throughout the body but matters most in neurons (nerve cells). Its exact job is not fully understood, but it acts as a scaffold: it helps move cargo along the inside of neurons and supports the transport of BDNF (brain-derived neurotrophic factor), a survival signal that keeps certain brain cells alive. Normal huntingtin is essential: in mice, removing it completely stops the embryo from developing. So the gene itself is vital; the disease comes from a specific harmful change, not from losing the gene.

The CAG repeat expansion

The disease-causing change is an expansion of the CAG repeat near the start of HTT. Because CAG is the codon for glutamine, a longer repeat means a longer run of glutamines (a polyglutamine tract) inside huntingtin. A normal allele carries roughly fewer than 27 repeats. 40 or more reliably causes disease, while 36 to 39 shows reduced penetrance, meaning a person in this range may or may not develop symptoms within a normal lifespan (so 36 is not as certain as 40+). The overlong polyQ tract makes the protein misfold and stick together into clumps (aggregates) inside neurons. This is a toxic gain of function: the mutant protein actively harms cells, hitting the striatum (a movement-control region deep in the brain) hardest.

But how do we know?

George Huntington described the disease in 1872. The gene's location was found in 1983 by linkage to a marker on chromosome 4 (the first disease gene mapped this way), using large affected families including the Venezuela / Lake Maracaibo cohort studied by Nancy Wexler and collaborators. In 1993, the Huntington's Disease Collaborative Research Group identified HTT itself and showed the mutation was an expanded CAG repeat, directly linking repeat length to the disease.

Inheritance pattern

Huntington's is autosomal dominant: a single expanded HTT allele is enough to cause disease, so each child of an affected parent has a 50% chance of inheriting it at each pregnancy through meiosis. The repeat is unstable when passed on, especially through the father. It can grow longer between generations, and because longer repeats mean earlier onset, the disease can appear at a younger age in successive generations, a pattern called anticipation. Because the exact mutation is known, a predictive genetic test on a single person's DNA can reveal carrier status years before symptoms, though many at-risk people choose not to take it.

Clinical & research importance

HTT is a landmark in genetics for two reasons. First, it was the first disease gene located by linkage to an anonymous DNA marker (1983), proving that a gene could be found from its inheritance pattern alone, the strategy that later powered the genome era. Second, it became the model case for predictive testing: because the test reveals an incurable, adult-onset outcome, it forced medicine to develop careful counselling and to respect the right not to know. Current research focuses on huntingtin-lowering therapies rather than editing the DNA itself. Both main approaches target the huntingtin mRNA (the gene's message) so the protein is never made: an antisense oligonucleotide is a short synthetic strand that pairs with the mRNA and flags it for destruction, while RNA interference feeds a small double-stranded RNA into the cell's own silencing machinery to cut the same message.

Key facts

The mutation is an expanded CAG repeat in HTT, which lengthens a run of glutamine in the huntingtin protein.
40 or more repeats reliably causes disease; 36 to 39 shows reduced penetrance (may or may not cause symptoms); repeat length is inversely correlated with age of onset.
Autosomal dominant: each child of an affected parent has a 50% chance of inheriting the expansion.
The repeat can grow when passed on (especially from the father), causing anticipation, earlier onset in later generations.
A predictive test on one person's DNA can reveal carrier status before symptoms; there is still no cure, though huntingtin-lowering therapies are in trials.

Connect to the app

This gene ties the Family Saga to the science: see how a dominant allele segregates at meiosis (50% per child), and how a repeat-expansion mutation differs from a single-letter change in the When things change module.

HTT