HD Biology for Dummies

Patterns of Inheritance

Genes determine biological traits. The nature of the gene determines the nature of the trait. A mutant gene, such as the gene for HD, produces an aberrant trait.

You have two copies of every human gene, one copy inherited from each of your parents. (Except for the genes on the X and Y chromosomes if you're male.) The mutant gene for HD is said to be "dominant" because you only need to have inherited one copy from one parent to produce the disease. Mutant genes for other inherited diseases (such as cystic fibrosis) are "recessive"; to develop CF, you must inherit mutant gene copies from both of your parents. It is because the HD mutation is dominant that the children of a person with HD are 50% at risk for having inherited the HD mutation.

Nature of the Gene

Biological activities are carried out by proteins. Proteins are constructed by linking together a chain of amino acids. Proper functioning of a protein requires a particular chain of amino acids assembled in a particular order.

DNA is also a chain of simpler subunits, the familiar nucleotides A, T, C and G. A gene is the sequence of nucleotides that is translated into the particular sequence of amino acids that makes up a protein. The rule of nucleotide to amino acid translation says that each amino acid is encoded by a particular sequence - a "codon" - of three DNA nucleotides. If you are familiar with HD, you already know one of these codons: the DNA sequence CAG encodes the amino acid glutamine.

A mutant gene is a gene where the sequence of DNA nucleotides has been changed so that it is no longer translated into the sequence of amino acids that produces a properly functioning protein.

Huntingtin and CAG Repeats

The protein affected by the HD mutation is called huntingtin, by reference to its involvement with HD. The normal function of huntingtin is not well understood.

In one part of the chain of amino acids that make up huntingtin there is a long string of the amino acid glutamine. In "normal" huntingtin, that string is 12-34 glutamines long. In DNA, the amino acid glutamine is encoded by the nucleotide sequence CAG. Hence, the gene for huntingtin typically contains the equence "CAG" repeated 12-25 times; this is the "CAG repeat". Expansion of the CAG repeat beyond 35 is the mutation that causes HD, meaning that the "mutant" huntingtin produced in the cells of a person with HD contains A string of >35 glutamines. Actually, HD is said to show "incomplete penetrance" at CAG repeats between 35 and 41; this means that some people with huntingtin genes in that range do not develop HD within a normal lifespan. Interestingly, other neurological disorders have also been associated with proteins having excessively long strings of glutamine.

Due to errors that may occur when DNA is copied during formation of egg and sperm cells, the CAG repeat may expand. A person with a huntingtin gene in the normal CAG range may thus have children with a huntingtin gene in the mutant range. This process, which is more likely to occur in males, may account for the incidence of HD in families where the disease was previously unknown.

Understanding the Disease Process

Since the genetic mutation that causes HD was revealed, research has focused on how the presence of mutant huntingtin in cells disrupts the normal function of brain cells. It has been learned that the expanded sequence of glutamines changes how huntingtin associates with other proteins in cells. Depending on the normal functions of those other proteins, this can have a profound impact on cell function. There is evidence that mutant huntingtin may modify patterns of gene expression - that is, what proteins are produced by cells and in what amounts. Protein-protein interaction is also responsible for formation of the aggregates seen in neurons of persons with HD and in mice engineered to produce the expanded glutamine tract; at present, it isn't known whether those aggregates contribute to the disease process.

HD Biology and Therapy

The ultimate goal of understanding HD biology is to develop interventions that block or reverse the disease process. Knowing more about how mutant huntingtin associates with proteins could lead to the design of drugs that disrupt those associations. It may even be possible, using gene therapy, to block production of mutant huntingtin in the first place.

Alternately, HD might be attacked indirectly by concentrating on the consequences of mutant huntingtin action. It is known that cells producing mutant huntingtin show changes in cellular energy metabolism; in fact, animals exposed to a particular respiratory poison suffer a pattern of brain damage very similar to that seen in HD. Cells producing mutant huntingtin also seem to be especially susceptible to apoptosis, or "programmed cell death". Improving neuronal energy metabolism or inhibiting apoptosis in neurons may slow the progress of HD.

Overview of Huntington's Disease

Published by GeneClinics.

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Causes of HD

Published by HOPES (Huntington's Outreach Project for Education, at Stanford)

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Huntington's Disease Overview

Published by the Huntington Study Group

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What causes HD?

Published by the National Institute of Neurological Disorders and Stroke (NINDS)

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Huntington's Disease: Literature Review

Published by the National Center for Biotechnology Information

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