Editing Huntington's disease (section)

===Genetic mutation===

HD is one of several [[trinucleotide repeat disorder]]s that are caused by the length of a repeated section of a gene exceeding a normal range.<ref name="lancet07" /> The ''HTT'' gene is located on the [[Locus (genetics)|short arm]] of [[chromosome 4 (human)|chromosome 4]]<ref name="lancet07" /> at 4p16.3. ''HTT'' contains a sequence of three [[DNA base]]s—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e.&nbsp;... CAGCAGCAG&nbsp;...), known as a trinucleotide repeat.<ref name="lancet07" /> CAG is the three-letter [[genetic code]] ([[codon]]) for the [[amino acid]] [[glutamine]], so a series of them results in the production of a chain of glutamine known as a [[polyglutamine tract]] (or polyQ tract), and the repeated part of the gene, the ''polyQ region''.<ref>{{cite journal | vauthors = Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Tanaka F, Adachi H, Sobue G | title = Molecular genetics and biomarkers of polyglutamine diseases | journal = Current Molecular Medicine | volume = 8 | issue = 3 | pages = 221–234 | date = May 2008 | pmid = 18473821 | doi = 10.2174/156652408784221298 }}</ref>
[[File:Huntington's disease (5880985560).jpg|thumb|upright=1.4|Graphic showing at top normal range of repeats, and disease-causing range of repeats.]]

{| class="wikitable" style="float:right; margin-left:15px; margin-right:15px; text-align:center;"
|+Classification of trinucleotide repeats, and resulting disease status, depending on the number of CAG repeats<ref name="lancet07" />
|-
! Repeat count
! Classification
! Disease status
! Risk to offspring
|-
| <27
| Normal
| Will not be affected
| None
|-
| 27–35
| Intermediate
| Will not be affected
| Elevated, but <50%
|-
| 36–39
| Reduced Penetrance
| May or may not be affected
| 50%
|-
| 40+
| Full penetrance
| Will be affected
| 50%
|}

Generally, people have fewer than 36 repeated glutamines in the polyQ region, which results in the production of the [[cytoplasmic]] protein huntingtin.<ref name="lancet07" /> However, a sequence of 36 or more glutamines results in the production of a protein with different characteristics.<ref name="lancet07" /> This altered form, called mutant huntingtin (mHtt), increases the decay rate of certain types of [[medium spiny neurons|neurons]]. Regions of the brain have differing amounts and reliance on these types of neurons and are affected accordingly.<ref name="lancet07" /> Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to the environment and other genes that modify the mechanism of HD.<ref name="lancet07" /> About 36 to 39 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. In some cases, the onset may be so late that symptoms are never noticed.<ref name="lancet07" /> With very large repeat counts (more than 60), HD onset can occur below the age of 20, known as juvenile HD. Juvenile HD is typically of the Westphal variant that is characterized by slowness of movement, rigidity, and tremors. This accounts for about 7% of HD carriers.<ref name="Squitieri">{{cite journal | vauthors = Squitieri F, Frati L, Ciarmiello A, Lastoria S, Quarrell O | title = Juvenile Huntington's disease: does a dosage-effect pathogenic mechanism differ from the classical adult disease? | journal = Mechanisms of Ageing and Development | volume = 127 | issue = 2 | pages = 208–212 | date = February 2006 | pmid = 16274727 | doi = 10.1016/j.mad.2005.09.012 | s2cid = 20523093 }}</ref><ref name="juvenile">{{cite journal | vauthors = Nance MA, Myers RH | title = Juvenile onset Huntington's disease--clinical and research perspectives | journal = Mental Retardation and Developmental Disabilities Research Reviews | volume = 7 | issue = 3 | pages = 153–157 | year = 2001 | pmid = 11553930 | doi = 10.1002/mrdd.1022 }}</ref>