Просмотр кода страницы Haploinsufficiency

{{Short description|Concept in genetics}}
{{more citations needed|date=February 2019}}
[[File:Haploinsufficiency graph only.jpg|thumb|Haploinsufficiency model of dominant genetic disorders.  ''A''<sup>+</sup> is a normal allele.  ''A''<sup>−</sup> is a mutant allele with little or no function.  In haplosufficiency (most genes), a single normal allele provides enough function, so ''A''<sup>+</sup>''A''<sup>−</sup> individuals are healthy.  In haploinsufficiency, a single normal allele does not provide enough function, so ''A''<sup>+</sup>''A''<sup>−</sup> individuals have a genetic disorder.
]]

'''Haploinsufficiency''' in [[genetics]] describes a model of [[Dominance (genetics)|dominant]] gene action in [[diploid]] organisms, in which a single copy of the [[wild-type]] [[allele]] at a [[Locus (genetics)|locus]] in [[heterozygous]] combination with a variant allele is insufficient to produce the wild-type [[phenotype]]. Haploinsufficiency may arise from a ''de novo'' or inherited [[loss-of-function mutation]] in the variant allele, such that it yields little or no gene product (often a [[protein]]). Although the other, standard allele still produces the standard amount of product, the total product is insufficient to produce the standard phenotype. This [[heterozygous]] [[genotype]] may result in a non- or sub-standard, deleterious, and (or) disease phenotype. Haploinsufficiency is the standard explanation for dominant deleterious alleles.{{clarify|date=July 2020}}

In the alternative case of '''haplosufficiency''', the loss-of-function allele behaves as above, but the single standard allele in the [[heterozygous]] genotype produces sufficient gene product to produce the same, standard phenotype as seen in the [[homozygote]]. Haplosufficiency accounts for the typical dominance of the "standard" allele over variant alleles, where the phenotypic identity of genotypes heterozygous and homozygous for the allele defines it as dominant, ''versus'' a variant phenotype produced only by the genotype homozygous for the alternative allele, which defines it as recessive.

== Mechanism ==

The alteration in the [[gene dosage]], which is caused by the loss of a functional allele, is also called allelic insufficiency.

== Haploinsufficiency in humans ==
About 3,000 human genes cannot tolerate loss of one of the two alleles.<ref>{{Cite journal |last1=Bartha |first1=István |last2=di Iulio |first2=Julia |last3=Venter |first3=J. Craig |last4=Telenti |first4=Amalio |date=January 2018 |title=Human gene essentiality |url=http://www.nature.com/articles/nrg.2017.75 |journal=Nature Reviews Genetics |language=en |volume=19 |issue=1 |pages=51–62 |doi=10.1038/nrg.2017.75 |pmid=29082913 |s2cid=9025172 |issn=1471-0056|url-access=subscription }}</ref>

An example of this is seen in the case of [[Williams syndrome]], a neurodevelopmental disorder caused by the haploinsufficiency of genes at 7q11.23. The haploinsufficiency is caused by the [[copy-number variation]] (CNV) of 28 genes led by the deletion of ~1.6 Mb. These dosage-sensitive genes are vital for human language and constructive cognition.<ref>{{Cite journal |last1=Tassabehji |first1=M. |last2=Metcalfe |first2=K. |last3=Karmiloff-Smith |first3=A. |last4=Carette |first4=M. J. |last5=Grant |first5=J. |last6=Dennis |first6=N. |last7=Reardon |first7=W. |last8=Splitt |first8=M. |last9=Read |first9=A. P. |last10=Donnai |first10=D. |date=January 1999 |title=Williams syndrome: use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes |journal=American Journal of Human Genetics |volume=64 |issue=1 |pages=118–125 |doi=10.1086/302214 |issn=0002-9297 |pmc=1377709 |pmid=9915950}}</ref>

Another example is the haploinsufficiency of [[telomerase reverse transcriptase]] which leads to anticipation in autosomal dominant [[dyskeratosis congenita]]. It is a rare inherited disorder characterized by abnormal skin manifestations, which results in [[bone marrow failure]], [[pulmonary fibrosis]] and an increased predisposition to cancer. A [[null mutation]] in motif D of the reverse transcriptase domain of the telomerase protein, hTERT, leads to this phenotype. Thus telomerase dosage is important for maintaining tissue proliferation.<ref>{{cite journal| last1= Armanios| first1= M. |display-authors= etal| year= 2004| title= Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenital| journal= [[Genetics (journal)|Genetics]]| volume= 102| number= 44| pages= 15960–15964}}</ref>

A variation of haploinsufficiency exists for mutations in the gene ''[[PRPF31]]'', a known cause of [[autosomal dominant]] [[retinitis pigmentosa]]. There are two wild-type alleles of this gene—a high-[[expressivity (genetics)|expressivity]] allele and a low-expressivity allele. When the mutant gene is inherited with a high-expressivity allele, there is no disease phenotype. However, if a mutant allele and a low-expressivity allele are inherited, the residual protein levels falls below that required for normal function, and disease phenotype is present.<ref>{{cite journal| last1=McGee| first1= TL| last2= Devoto | first2= M| last3= Ott| first3= J| author4= Berson EL| author5= Dryja TP| display-authors= 3| title= Evidence that the penetrance of mutations at the RP11 locus causing dominant retinitis pigmentosa is influenced by a gene linked to the homologous RP11 allele| journal= Am J Hum Genet| date= November 1997| volume= 61| number= 5| pages= 1059–66| doi= 10.1086/301614| pmid= 9345108| pmc= 1716046}}</ref>

[[Copy number variation]] (CNV) refers to the differences in the number of copies of a particular region of the genome. This leads to too many or too few of the dosage sensitive genes. The genomic rearrangements, that is, deletions or duplications, are caused by the mechanism of [[non-allelic homologous recombination]] (NAHR). In the case of the Williams Syndrome, the microdeletion includes the ''[[ELN (gene)|ELN]]'' gene. The hemizygosity of the elastin is responsible for [[aortic stenosis|supravalvular aortic stenosis]], the obstruction in the left ventricular outflow of blood in the heart.<ref>{{cite journal| last1= Lee| first1= J. A. |last2= Lupski| first2= J. R. |title= Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders| journal= [[Neuron (journal)|Neuron]] | number= 52| pages= 103–121 |year= 2006| volume= 52 | doi= 10.1016/j.neuron.2006.09.027 | pmid= 17015230 | s2cid= 22412305 | doi-access= free }}</ref><ref>{{cite journal| last1= Menga| first1= X.| last2= Lub| first2= X.| last3= Morrisc| first3= C.A. |last4= Keating| first4= M.T.| title= A Novel Human GeneFKBP6Is Deleted in Williams Syndrome*1| journal= [[Genomics (journal)|Genomics]] |number= 52| pages= 130–137 |year= 1998| volume= 52| doi= 10.1006/geno.1998.5412| pmid= 9782077}}</ref>

'''Other examples include:'''
* Some [[cancer]]s
* [[1q21.1 deletion syndrome]]
* 5q- syndrome in [[myelodysplastic syndrome|myelodysplastic syndrome (MDS)]]
* [[22q11.2 deletion syndrome]]
* [[CHARGE syndrome]]
* [[Cleidocranial dysostosis]]
* [[Ehlers–Danlos syndrome]]
* [[Frontotemporal dementia]] caused by mutations in [[progranulin]]
* [[GLUT1 deficiency|GLUT1 deficiency (DeVivo syndrome)]]<ref name="pmid20687207">{{cite journal| author1=Rotstein M, Engelstad K, Yang H| author2= Wang D, Levy B, Chung WK | display-authors=1| title=Glut1 deficiency: inheritance pattern determined by haploinsufficiency. | journal=Ann Neurol | year= 2010 | volume= 68 | issue= 6 | pages= 955–8 | pmid=20687207 | doi=10.1002/ana.22088 | pmc=2994988 }}</ref>
* [[Haploinsufficiency of A20]]
* Haploinsufficiency of [[Proline-rich 12|PRR12]]<ref>{{Cite journal |last=Chowdhury |first=Fuad |last2=Wang |first2=Lei |last3=Al-Raqad |first3=Mohammed |last4=Amor |first4=David J. |last5=Baxová |first5=Alice |last6=Bendová |first6=Šárka |last7=Biamino |first7=Elisa |last8=Brusco |first8=Alfredo |last9=Caluseriu |first9=Oana |last10=Cox |first10=Nancy J. |last11=Froukh |first11=Tawfiq |last12=Gunay-Aygun |first12=Meral |last13=Hančárová |first13=Miroslava |last14=Haynes |first14=Devon |last15=Heide |first15=Solveig |date=July 2021 |title=Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities |url=https://doi.org/10.1038/s41436-021-01129-6 |journal=Genetics in Medicine |volume=23 |issue=7 |pages=1234–1245 |doi=10.1038/s41436-021-01129-6 |issn=1098-3600|hdl=2318/1808620 |hdl-access=free }}</ref><ref>{{Cite web |last=Steinbuch |first=Yaron |date=2024-02-08 |title=Baby born without eyes due to rare genetic disorder |url=https://nypost.com/2024/02/08/news/baby-born-without-eyes-due-to-rare-genetic-disorder/ |access-date=2024-02-09 |language=en-US}}</ref>
* [[Holoprosencephaly]] caused by haploinsufficiency in the [[Sonic Hedgehog|Sonic Hedgehog gene]]
* [[Holt–Oram syndrome]]
* [[Marfan syndrome]]<ref>{{Cite journal |last1=Robinson |first1=P. N. |last2=Arteaga-Solis |first2=E. |last3=Baldock |first3=C. |last4=Collod-Béroud |first4=G. |last5=Booms |first5=P. |last6=De Paepe |first6=A. |last7=Dietz |first7=H. C. |last8=Guo |first8=G. |last9=Handford |first9=P. A. |last10=Judge |first10=D. P. |last11=Kielty |first11=C. M. |last12=Loeys |first12=B. |last13=Milewicz |first13=D. M. |last14=Ney |first14=A. |last15=Ramirez |first15=F. |date=2006-03-29 |title=The molecular genetics of Marfan syndrome and related disorders |journal=Journal of Medical Genetics |volume=43 |issue=10 |pages=769–787 |doi=10.1136/jmg.2005.039669 |issn=1468-6244 |pmc=2563177 |pmid=16571647}}</ref>
* [[Phelan–McDermid syndrome]]
* [[Polydactyly]]
* [[Dravet Syndrome]]
* [[ZTTK]]
* [[FOXP1]] Syndrome
* [[NR4A2-related syndrome]]

== Methods of detection ==
The most direct method to detect haploinsufficiency is the [[Zygosity|heterozygous]] deletion of one [[allele]] in a model organism. This can be done in [[Tissue culture|tissue culture cells]] or in single-celled organisms such as yeast (''[[Saccharomyces cerevisiae]]'').<ref>{{Cite journal |last1=Strome |first1=Erin D. |last2=Wu |first2=Xiaowei |last3=Kimmel |first3=Marek |last4=Plon |first4=Sharon E. |date=March 2008 |title=Heterozygous screen in Saccharomyces cerevisiae identifies dosage-sensitive genes that affect chromosome stability |journal=Genetics |volume=178 |issue=3 |pages=1193–1207 |doi=10.1534/genetics.107.084103 |issn=0016-6731 |pmc=2278055 |pmid=18245329}}</ref>

==References==
{{Reflist}}

== Further reading ==
* {{cite journal| last1= Ebert| first1= BL| display-authors= etal| year= 2008| title= Identification of RPS14 as a 5q- syndrome gene by RNA interference screen| journal= [[Nature (journal)|Nature]] | volume= 451| number= 451| pages=335–340| doi= 10.1038/nature06494| pmid= 18202658| pmc= 3771855| bibcode= 2008Natur.451..335E}}
* {{cite book| last1= Griffiths| first1= Anthony J.| display-authors= etal| year=200| title= Introduction to Genetic Analysis | edition= 8th| publisher= W.H. Freeman |isbn= 0-7167-4939-4}}

{{Commons category|Haploinsufficiency}}

[[Category:Genetics]]
[[Category:Rare diseases]]