Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-typeallele at a 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 heterozygousgenotype may result in a non- or sub-standard, deleterious, and (or) disease phenotype. Haploinsufficiency is the standard explanation for dominant deleterious alleles.[clarification needed]
Haploinsufficiency model of dominant genetic disorders. A+ is a normal allele. A− is a mutant allele with little or no function. In haplosufficiency (most genes), a single normal allele provides enough function, so A+A− individuals are healthy. In haploinsufficiency, a single normal allele does not provide enough function, so A+A− individuals have a genetic disorder.
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.
The alteration in the gene dosage, which is caused by the loss of a functional allele, is also called allelic insufficiency.
Haploinsufficiency in humansedit
About 3,000 human genes cannot tolerate loss of one of the two alleles.[1]
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.[2]
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.[3]
A variation of haploinsufficiency exists for mutations in the gene PRPF31, a known cause of autosomal dominantretinitis pigmentosa. There are two wild-type alleles of this gene—a high-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.[4]
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. The hemizygosity of the elastin is responsible for supravalvular aortic stenosis, the obstruction in the left ventricular outflow of blood in the heart.[5][6]
^Tassabehji, M.; Metcalfe, K.; Karmiloff-Smith, A.; Carette, M. J.; Grant, J.; Dennis, N.; Reardon, W.; Splitt, M.; Read, A. P.; Donnai, D. (January 1999). "Williams syndrome: use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes". American Journal of Human Genetics. 64 (1): 118–125. doi:10.1086/302214. ISSN 0002-9297. PMC1377709. PMID 9915950.
^Armanios, M.; et al. (2004). "Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenital". Genetics. 102 (44): 15960–15964.
^McGee, TL; Devoto, M; Ott, J; et al. (November 1997). "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". Am J Hum Genet. 61 (5): 1059–66. doi:10.1086/301614. PMC1716046. PMID 9345108.
^Lee, J. A.; Lupski, J. R. (2006). "Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders". Neuron. 52 (52): 103–121. doi:10.1016/j.neuron.2006.09.027. PMID 17015230. S2CID 22412305.
^Menga, X.; Lub, X.; Morrisc, C.A.; Keating, M.T. (1998). "A Novel Human GeneFKBP6Is Deleted in Williams Syndrome*1". Genomics. 52 (52): 130–137. doi:10.1006/geno.1998.5412. PMID 9782077.
^Rotstein M, Engelstad K, Yang H; et al. (2010). "Glut1 deficiency: inheritance pattern determined by haploinsufficiency". Ann Neurol. 68 (6): 955–8. doi:10.1002/ana.22088. PMC2994988. PMID 20687207.{{cite journal}}: CS1 maint: multiple names: authors list (link)
^Chowdhury, Fuad; Wang, Lei; Al-Raqad, Mohammed; Amor, David J.; Baxová, Alice; Bendová, Šárka; Biamino, Elisa; Brusco, Alfredo; Caluseriu, Oana; Cox, Nancy J.; Froukh, Tawfiq; Gunay-Aygun, Meral; Hančárová, Miroslava; Haynes, Devon; Heide, Solveig (July 2021). "Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities". Genetics in Medicine. 23 (7): 1234–1245. doi:10.1038/s41436-021-01129-6. ISSN 1098-3600.
^Steinbuch, Yaron (2024-02-08). "Baby born without eyes due to rare genetic disorder". Retrieved 2024-02-09.
^Robinson, P. N.; Arteaga-Solis, E.; Baldock, C.; Collod-Béroud, G.; Booms, P.; De Paepe, A.; Dietz, H. C.; Guo, G.; Handford, P. A.; Judge, D. P.; Kielty, C. M.; Loeys, B.; Milewicz, D. M.; Ney, A.; Ramirez, F. (2006-03-29). "The molecular genetics of Marfan syndrome and related disorders". Journal of Medical Genetics. 43 (10): 769–787. doi:10.1136/jmg.2005.039669. ISSN 1468-6244. PMC2563177. PMID 16571647.
Ebert, BL; et al. (2008). "Identification of RPS14 as a 5q- syndrome gene by RNA interference screen". Nature. 451 (451): 335–340. Bibcode:2008Natur.451..335E. doi:10.1038/nature06494. PMC3771855. PMID 18202658.
Griffiths, Anthony J.; et al. (200). Introduction to Genetic Analysis (8th ed.). W.H. Freeman. ISBN0-7167-4939-4.
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This article needs additional citations for verification Please help improve this article by adding citations to reliable sources Unsourced material may be challenged and removed Find sources Haploinsufficiency news newspapers books scholar JSTOR February 2019 Learn how and when to remove this template message Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms in which a single copy of the wild type allele at a 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 clarification needed Haploinsufficiency model of dominant genetic disorders A is a normal allele A is a mutant allele with little or no function In haplosufficiency most genes a single normal allele provides enough function so A A individuals are healthy In haploinsufficiency a single normal allele does not provide enough function so A A individuals have a genetic disorder 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 Contents 1 Mechanism 2 Haploinsufficiency in humans 3 Methods of detection 4 References 5 Further readingMechanism editThe alteration in the gene dosage which is caused by the loss of a functional allele is also called allelic insufficiency Haploinsufficiency in humans editAbout 3 000 human genes cannot tolerate loss of one of the two alleles 1 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 2 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 3 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 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 4 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 The hemizygosity of the elastin is responsible for supravalvular aortic stenosis the obstruction in the left ventricular outflow of blood in the heart 5 6 Other examples include Some cancers 1q21 1 deletion syndrome 5q syndrome in myelodysplastic syndrome MDS 22q11 2 deletion syndrome CHARGE syndrome Cleidocranial dysostosis Ehlers Danlos syndrome Frontotemporal dementia caused by mutations in progranulin GLUT1 deficiency DeVivo syndrome 7 Haploinsufficiency of A20 Haploinsufficiency of PRR12 8 9 Holoprosencephaly caused by haploinsufficiency in the Sonic Hedgehog gene Holt Oram syndrome Marfan syndrome 10 Phelan McDermid syndrome Polydactyly Dravet Syndrome ZTTK FOXP1 Syndrome NR4A2 related syndromeMethods of detection editThe most direct method to detect haploinsufficiency is the heterozygous deletion of one allele in a model organism This can be done in tissue culture cells or in single celled organisms such as yeast Saccharomyces cerevisiae 11 References edit Bartha Istvan di Iulio Julia Venter J Craig Telenti Amalio January 2018 Human gene essentiality Nature Reviews Genetics 19 1 51 62 doi 10 1038 nrg 2017 75 ISSN 1471 0056 PMID 29082913 S2CID 9025172 Tassabehji M Metcalfe K Karmiloff Smith A Carette M J Grant J Dennis N Reardon W Splitt M Read A P Donnai D January 1999 Williams syndrome use of chromosomal microdeletions as a tool to dissect cognitive and physical phenotypes American Journal of Human Genetics 64 1 118 125 doi 10 1086 302214 ISSN 0002 9297 PMC 1377709 PMID 9915950 Armanios M et al 2004 Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenital Genetics 102 44 15960 15964 McGee TL Devoto M Ott J et al November 1997 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 Am J Hum Genet 61 5 1059 66 doi 10 1086 301614 PMC 1716046 PMID 9345108 Lee J A Lupski J R 2006 Genomic rearrangements and gene copy number alterations as a cause of nervous system disorders Neuron 52 52 103 121 doi 10 1016 j neuron 2006 09 027 PMID 17015230 S2CID 22412305 Menga X Lub X Morrisc C A Keating M T 1998 A Novel Human GeneFKBP6Is Deleted in Williams Syndrome 1 Genomics 52 52 130 137 doi 10 1006 geno 1998 5412 PMID 9782077 Rotstein M Engelstad K Yang H et al 2010 Glut1 deficiency inheritance pattern determined by haploinsufficiency Ann Neurol 68 6 955 8 doi 10 1002 ana 22088 PMC 2994988 PMID 20687207 a href Template Cite journal html title Template Cite journal cite journal a CS1 maint multiple names authors list link Chowdhury Fuad Wang Lei Al Raqad Mohammed Amor David J Baxova Alice Bendova Sarka Biamino Elisa Brusco Alfredo Caluseriu Oana Cox Nancy J Froukh Tawfiq Gunay Aygun Meral Hancarova Miroslava Haynes Devon Heide Solveig July 2021 Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental eye and multisystem abnormalities Genetics in Medicine 23 7 1234 1245 doi 10 1038 s41436 021 01129 6 ISSN 1098 3600 Steinbuch Yaron 2024 02 08 Baby born without eyes due to rare genetic disorder Retrieved 2024 02 09 Robinson P N Arteaga Solis E Baldock C Collod Beroud G Booms P De Paepe A Dietz H C Guo G Handford P A Judge D P Kielty C M Loeys B Milewicz D M Ney A Ramirez F 2006 03 29 The molecular genetics of Marfan syndrome and related disorders Journal of Medical Genetics 43 10 769 787 doi 10 1136 jmg 2005 039669 ISSN 1468 6244 PMC 2563177 PMID 16571647 Strome Erin D Wu Xiaowei Kimmel Marek Plon Sharon E March 2008 Heterozygous screen in Saccharomyces cerevisiae identifies dosage sensitive genes that affect chromosome stability Genetics 178 3 1193 1207 doi 10 1534 genetics 107 084103 ISSN 0016 6731 PMC 2278055 PMID 18245329 Further reading editEbert BL et al 2008 Identification of RPS14 as a 5q syndrome gene by RNA interference screen Nature 451 451 335 340 Bibcode 2008Natur 451 335E doi 10 1038 nature06494 PMC 3771855 PMID 18202658 Griffiths Anthony J et al 200 Introduction to Genetic Analysis 8th ed W H Freeman ISBN 0 7167 4939 4 nbsp Wikimedia Commons has media related to Haploinsufficiency Retrieved from https en wikipedia org w index php title Haploinsufficiency amp oldid 1205172403, wikipedia, wiki, book, books, library,
