Editing Frameshift mutation (section)

==Diseases==
Several diseases have frameshift mutations as at least part of the cause. Knowing prevalent mutations can also aid in the diagnosis of the disease. Currently there are attempts to use frameshift mutations beneficially in the treatment of diseases, changing the reading frame of the amino acids.
[[File:mutations on BRCA1.jpg|250px|thumb|Frequency of mutations on BRCA1 gene on chromosome 17]]
[[File:mutations on BRCA2.jpg|250px|thumb|Frequency of mutations on BRCA2 gene on chromosome 13]]

===Cancer===

{{Main article|cancer}}

Frameshift mutations are known to be a factor in [[colorectal]] cancer as well as other [[cancers]] with [[microsatellite instability]]. As stated previously, frameshift mutations are more likely to occur in a region of repeat sequence. When DNA mismatch repair does not fix the addition or deletion of bases, these mutations are more likely to be pathogenic. This may be in part because the tumor is not told to stop growing. Experiments in yeast and bacteria help to show characteristics of microsatellites that may contribute to defective DNA mismatch repair. These include the length of the [[microsatellite]], the makeup of the genetic material and how pure the repeats are. Based on experimental results longer microsatellites have a higher rate of frameshift mutations. The flanking DNA can also contribute to frameshift mutations.<ref name="microsatellite instability">{{cite journal|last=Schmoldt|first=A|author2=Benthe, HF|author3=Haberland, G|title=Digitoxin metabolism by rat liver microsomes |journal=Biochemical Pharmacology|date=1 September 1975|volume=24|issue=17|pages=1639–41 |pmid=10 |doi=10.1016/0006-2952(75)90094-5 |url=https://serval.unil.ch/notice/serval:BIB_EE7D4CC5FB04|hdl=10033/333424|hdl-access=free}}</ref> In prostate cancer a frameshift mutation changes the [[open reading frame]] (ORF) and prevents [[apoptosis]] from occurring. This leads to an unregulated growth of the [[tumor]]. While there are environmental factors that contribute to the progression of [[prostate cancer]], there is also a genetic component. During testing of coding regions to identify mutations, 116 genetic variants were discovered, including 61 frameshift mutations.<ref name="somatic mutations in prostate cancer">{{cite journal|last=Xu|first=XiaoLin|author2=Zhu, KaiChang|author3=Liu, Feng|author4=Wang, Yue|author5=Shen, JianGuo|author6=Jin, Jizhong|author7=Wang, Zhong|author8=Chen, Lin|author9=Li, Jiadong|author10= Xu, Min|title=Identification of somatic mutations in human prostate cancer by RNA-Seq|journal=Gene|doi=10.1016/j.gene.2013.01.046 |pmid=23434521 |volume=519|issue=2|date=May 2013|pages=343–7}}</ref> There are over 500 mutations on chromosome 17 that seem to play a role in the development of breast and ovarian cancer in the BRCA1 gene, many of which are frameshift.<ref name="cancer genomics">{{cite web|title=Cancer Genomics|url=http://www.cancer.gov/cancertopics/understandingcancer/cancergenomics/AllPages|publisher=National Cancer Institute at the National Institute of Health|access-date=24 March 2013|archive-date=18 March 2013|archive-url=https://web.archive.org/web/20130318041935/http://www.cancer.gov/cancertopics/understandingcancer/cancergenomics/allpages|url-status=dead}}</ref>

===Crohn's disease===

[[Crohn's disease]] has an association with the NOD2 gene. The mutation is an insertion of a [[Cytosine]] at position 3020. This leads to a premature stop codon, shortening the protein that is supposed to be transcribed. When the protein is able to form normally, it responds to bacterial liposaccharides, where the 3020insC mutation prevents the protein from being responsive.<ref>{{cite journal|vauthors=Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R, Britton H, Moran T, Karaliuskas R, Duerr RH, Achkar JP, Brant SR, Bayless TM, Kirschner BS, Hanauer SB, Nuñez G, Cho JH |title=A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.|journal=Nature|date=May 31, 2001|volume=411|issue=6837|pages=603–6|pmid=11385577|doi=10.1038/35079114|bibcode=2001Natur.411..603O|hdl=2027.42/62856|s2cid=205017657|url=https://deepblue.lib.umich.edu/bitstream/2027.42/62856/1/411603a0.pdf|hdl-access=free}}</ref>

===Cystic fibrosis===

[[Cystic fibrosis]] (CF) is a disease based on mutations in the CF [[transmembrane]] conductance regulator (CFTR) gene. There are over 1500 mutations identified, but not all cause the disease.<ref name="guidelines for CF">{{cite journal|vauthors=Farrell PM, Rosenstein BJ, White TB, Accurso FJ, Castellani C, Cutting GR, Durie PR, Legrys VA, Massie J, Parad RB, Rock MJ, Campbell PW |title=Guidelines for Diagnosis of Cystic Fibrosis in Newborns through Older Adults: Cystic Fibrosis Foundation Consensus Report|journal=The Journal of Pediatrics|volume=153|issue=2|pages=S4–S14|doi=10.1016/j.jpeds.2008.05.005 |pmid=18639722 |pmc=2810958 |year=2008}}</ref> Most cases of cystic fibrosis are a result of the ∆F508 mutation, which deletes the entire amino acid. Two frameshift mutations are of interest in diagnosing CF, CF1213delT and CF1154-insTC. Both of these mutations commonly occur in tandem with at least one other mutation. They both lead to a small decrease in the function of the [[lungs]] and occur in about 1% of patients tested. These mutations were identified through Sanger sequencing.<ref name="frameshift mutations in CF">{{cite journal|last=Iannuzzi|first=MC|author2=Stern, RC|author3=Collins, FS|author4=Hon, CT|author5=Hidaka, N|author6=Strong, T|author7=Becker, L|author8=Drumm, ML|author9=White, MB|author10= Gerrard, B|title=Two frameshift mutations in the cystic fibrosis gene.|journal=American Journal of Human Genetics|date=February 1991|volume=48|issue=2|pages=227–31|pmid=1990834|pmc=1683026}}</ref>

===HIV===

{{Main article|HIV/AIDS}}

[[CCR5]] is one of the cell entry co-factors associated with HIV, most frequently involved with nonsyncytium-inducing strains, is most apparent in HIV patients as opposed to AIDS patients. A 32 base pair deletion in CCR5 has been identified as a mutation that negates the likelihood of an HIV infection. This region on the open reading frame [[Open reading frame|ORF]] contains a frameshift mutation leading to a premature stop codon. This leads to the loss of the HIV-coreceptor function in vitro. CCR5-1 is considered the wild type and CCR5-2 is considered to be the mutant allele. Those with a heterozygous mutation for the CCR5 were less susceptible to the development of HIV. In a study, despite high exposure to the HIV virus, there was no one homozygous for the CCR5 mutation that tested positive for HIV.<ref name="HIV resistance"/>

===Tay–Sachs disease===

[[Tay–Sachs disease]] is a fatal disease affecting the central nervous system. It is most frequently found in infants and small children. Disease progression begins in the [[womb]] but symptoms do not appear until approximately 6 months of age. There is no cure for the disease.<ref name="tay sachs">{{cite web|title=Learning About Tay-Sachs Disease|url=http://www.genome.gov/10001220|publisher=National Human Genome Research Institute|access-date=24 March 2013}}</ref> Mutations in the β-hexosaminidase A (Hex A) gene are known to affect the onset of Tay-Sachs, with 78 mutations of different types being described, 67 of which are known to cause disease. Most of the mutations observed (65/78) are single base substitutions or SNPs, 11 deletions, 1 large and 10 small, and 2 insertions. 8 of the observed mutations are frameshift, 6 deletions and 2 insertions. A 4 base pair insertion in exon 11 is observed in 80% of Tay-Sachs disease presence in the [[Ashkenazi]] Jewish population. The frameshift mutations lead to an early stop codon which is known to play a role in the disease in infants. Delayed onset disease appears to be caused by 4 different mutations, one being a 3 base pair deletion.<ref name="Tay-Sachs mutations">{{cite journal|last=Myerowitz|first=R|title=Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene.|journal=Human Mutation|year=1997|volume=9|issue=3|pages=195–208|pmid=9090523 |doi=10.1002/(SICI)1098-1004(1997)9:3<195::AID-HUMU1>3.0.CO;2-7|doi-access=free}}</ref>

===Smith–Magenis syndrome===

[[Smith–Magenis syndrome]] (SMS) is a complex [[syndrome]] involving intellectual disabilities, sleep disturbance, behavioural problems, and a variety of craniofacial, skeletal, and visceral anomalies. The majority of SMS cases harbor an ~3.5 Mb common deletion that encompasses the retinoic acid induced-1 (''[[RAI1]]'') gene. Other cases illustrate variability in the SMS [[phenotype]] not previously shown for RAI1 mutation, including hearing loss, self-abusive behaviours, and mild global delays. Sequencing of RAI1 revealed mutation of a heptamericC-tract (CCCCCCC) in exon 3 resulting in frameshift mutations. Of the seven reported frameshift mutations occurring in poly C-tracts in RAI1, four cases (~57%) occur at this heptameric C-tract. The results indicate that this heptameric C-tract is a preferential [[recombination hotspot]] insertion/deletions (SNindels) and therefore a primary target for analysis in patients suspected for mutations in RAI1.<ref>{{cite journal|last=Truong|first=Hoa T|author2=Dudding, Tracy|author3= Blanchard, Christopher L.|author4= Elsea, Sarah H|title=Frameshift mutation hotspot identified in Smith-Magenis syndrome: case report and review of literature|journal=BMC Medical Genetics|volume=11|issue=1|page=142|doi=10.1186/1471-2350-11-142 |pmid=20932317 |pmc=2964533 |year=2010 |doi-access=free }}</ref>

===Hypertrophic cardiomyopathy===

[[Hypertrophic cardiomyopathy]] is the most common cause of [[sudden cardiac death|sudden death]] in young people, including trained athletes, and is caused by mutations in genes encoding proteins of the cardiac sarcomere. Mutations in the Troponin C gene (''[[TNNC1]]'') are a rare genetic cause of hypertrophic cardiomyopathy. A recent study has indicated that a frameshift mutation (c.363dupG or p.Gln122AlafsX30) in Troponin C was the cause of hypertrophic cardiomyopathy (and sudden cardiac death) in a 19-year-old male.<ref name="pmid21262074">{{cite journal |vauthors=Chung WK, Kitner C, Maron BJ |title=Novel frameshift mutation in Troponin C ( TNNC1) associated with hypertrophic cardiomyopathy and sudden death |journal=Cardiol Young |volume=21 |issue=3 |pages=345–8 |date=June 2011 |pmid=21262074 |doi=10.1017/S1047951110001927 |s2cid=46682245 }}</ref>

===Cures===
Finding a cure for the diseases caused by frameshift mutations is rare. Research into this is ongoing. One example is a [[primary immunodeficiency]] (PID), an inherited condition which can lead to an increase in infections. There are 120 genes and 150 mutations that play a role in primary immunodeficiencies. The standard treatment is currently '''gene therapy''', but this is a highly risky treatment and can often lead to other diseases, such as leukemia. Gene therapy procedures include modifying the zinc fringer nuclease fusion protein, cleaving both ends of the mutation, which in turn removes it from the sequence. Antisense-oligonucleotide mediated '''exon skipping''' is another possibility for Duchenne [[muscular dystrophy]]. This process allows for passing over the mutation so that the rest of the sequence remains in frame and the function of the protein stays intact. This, however, does not cure the disease, just treats symptoms, and is only practical in structural proteins or other repetitive genes. A third form of repair is '''revertant mosaicism''', which is naturally occurring by creating a reverse mutation or a mutation at a second site that corrects the reading frame. This reversion may happen by intragenic [[Genetic recombination|recombination]], [[mitotic]] gene conversion, second site DNA slipping or site-specific reversion. This is possible in several diseases, such as [[X-linked severe combined immunodeficiency]] (SCID), [[Wiskott–Aldrich syndrome]], and [[Bloom syndrome]]. There are no drugs or other pharmacogenomic methods that help with PIDs.<ref name="PID treatments">{{cite journal|last=Hu|first=Hailiang|author2=Gatti, Richard A|title=New approaches to treatment of primary immunodeficiencies: fixing mutations with chemicals|journal=Current Opinion in Allergy and Clinical Immunology|volume=8|issue=6|pages=540–6|doi=10.1097/ACI.0b013e328314b63b |pmid=18978469 |pmc=2686128 |year=2008}}</ref>

A European patent (EP1369126A1) in 2003 by Bork records a method used for prevention of cancers and for the curative treatment of cancers and precancers such as DNA-mismatch repair deficient (MMR) sporadic tumours and HNPCC associated tumours. The idea is to use '''immunotherapy''' with combinatorial mixtures of tumour-specific frameshift mutation-derived peptides to elicit a cytotoxic T-cell response specifically directed against tumour cells.<ref>European Patent [https://patents.google.com/patent/EP1369126A1/en] (December 10, 2003) "Use of coding microsatellite region frameshift mutation-derived peptides for treating cancer" by Bork ''et al''</ref>