Editing Huntington's disease (section)

==Genetics==
<!-- Please note that although the disorder is spelled Huntington, the associated gene and protein are correctly spelled Huntingtin -->
Everyone has two copies of the [[huntingtin gene]] (''HTT''), which codes for the [[huntingtin protein]] (Htt). ''HTT'' is also called the HD gene, and the ''IT15'' gene, (interesting [[transcription (genetics)|transcript]] 15). Part of this gene is a repeated section called a [[trinucleotide repeat expansion]] – a [[copy number variation#Types and chromosomal rearrangements|short repeat]], which varies in length between individuals, and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant huntingtin protein (mHtt). The differing functions of these proteins are the cause of pathological changes, which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant and almost fully [[penetrance|penetrant]]; mutation of either of a person's ''HTT'' alleles causes the disease. It is not inherited according to sex, but by the length of the repeated section of the gene; hence its severity can be influenced by the sex of the affected parent.<ref name="lancet07"/>

===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>

===Inheritance===

[[File:Autosomal Dominant Pedigree Chart2.svg|thumb|upright|right|alt=Diagram showing a father carrying the gene and an unaffected mother, leading to some of their offspring being affected; those affected are also shown with some affected offspring; those unaffected have no affected offspring|Huntington's disease is inherited in an [[autosomal dominant]] fashion. The probability of each offspring inheriting an affected gene is 50%. Inheritance is independent of sex, and the phenotype does not skip generations.]]

Huntington's disease has [[autosomal dominant]] inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant [[allele]]) from an affected parent.<ref name="lancet07" /> Since the penetrance of the mutation is very high, those who have a mutated copy of the gene will have the disease. In this type of inheritance pattern, each offspring of an affected individual has a 50% risk of inheriting the mutant allele and developing the disease (see figure). This probability is sex-independent since the huntingtin gene is not located on the X or Y chromosomes.<ref name="basicgenetics">{{cite book | vauthors =Passarge E | title=Color Atlas of Genetics | url =https://archive.org/details/coloratlasofgene0000pass | url-access =registration | publisher=Thieme | edition=2nd | year=2001 | page=[https://archive.org/details/coloratlasofgene0000pass/page/n155 142] | isbn=978-0-86577-958-7}}</ref><ref>{{Cite web |title=Sex Linked |url=https://www.genome.gov/genetics-glossary/Sex-Linked |access-date=2022-12-13 |website=Genome.gov |language=en |archive-date=14 April 2022 |archive-url=https://web.archive.org/web/20220414183337/https://www.genome.gov/genetics-glossary/Sex-Linked |url-status=live }}</ref>

[[Trinucleotide repeat expansion|Trinucleotide CAG repeats]] numbering over 28 are unstable during [[DNA replication|replication]], and this instability increases with the number of repeats present.<ref name="lancet07" /> This usually leads to new expansions as generations pass ([[dynamic mutation]]s) instead of reproducing an exact copy of the trinucleotide repeat.<ref name="lancet07" /> This causes the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28–35), or "reduced penetrance" (36–40), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD.<ref name="lancet07" /> The earlier [[age of onset]] and greater severity of disease in successive generations due to increases in the number of repeats is known as genetic [[anticipation (genetics)|anticipation]].<ref name="Day20152"/> Instability is greater in [[spermatogenesis]] than [[oogenesis]];<ref name="lancet07" /> maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length.<ref name="lancet07" /><ref name="Ridley">{{cite journal | vauthors = Ridley RM, Frith CD, Crow TJ, Conneally PM | title = Anticipation in Huntington's disease is inherited through the male line but may originate in the female | journal = Journal of Medical Genetics | volume = 25 | issue = 9 | pages = 589–595 | date = September 1988 | pmid = 2972838 | pmc = 1051535 | doi = 10.1136/jmg.25.9.589 }}</ref> Rarely is Huntington's disease caused by a [[de novo mutation|new mutation]], where neither parent has over 36 CAG repeats.<ref name="pmid16965319">{{cite journal | vauthors = Semaka A, Creighton S, Warby S, Hayden MR | title = Predictive testing for Huntington disease: interpretation and significance of intermediate alleles | journal = Clinical Genetics | volume = 70 | issue = 4 | pages = 283–294 | date = October 2006 | pmid = 16965319 | doi = 10.1111/j.1399-0004.2006.00668.x | s2cid = 26007984 }}</ref>

In the rare situations where both parents have an expanded HD gene, the risk increases to 75%, and when either parent has two expanded copies, the risk is 100%. Individuals with [[Homozygous|both genes affected]] are rare. For some time, HD was thought to be the only disease for which possession of a second mutated gene did not affect symptoms and progression,<ref name="pmid2881213">{{cite journal | vauthors = Wexler NS, Young AB, Tanzi RE, Travers H, Starosta-Rubinstein S, Penney JB, Snodgrass SR, Shoulson I, Gomez F, Ramos Arroyo MA | title = Homozygotes for Huntington's disease | journal = Nature | volume = 326 | issue = 6109 | pages = 194–197 | year = 1987 | pmid = 2881213 | doi = 10.1038/326194a0 | hdl-access = free | s2cid = 4312171 | bibcode = 1987Natur.326..194W | hdl = 2027.42/62543 }}</ref> but it has since been found that it can affect the [[phenotype]] and the rate of progression.<ref name="lancet07" /><ref name="pmid12615650">{{cite journal | vauthors = Squitieri F, Gellera C, Cannella M, Mariotti C, Cislaghi G, Rubinsztein DC, Almqvist EW, Turner D, Bachoud-Lévi AC, Simpson SA, Delatycki M, Maglione V, Hayden MR, Donato SD | title = Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course | journal = Brain | volume = 126 | issue = Pt 4 | pages = 946–955 | date = April 2003 | pmid = 12615650 | doi = 10.1093/brain/awg077 | doi-access = free }}</ref>