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Haploinsufficiency occurs when a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy does not produce enough of a gene product (typically a protein) to bring about a wild-type condition, leading to an abnormal or diseased state. It is responsible for some but not all autosomal dominant disorders.

Haplosufficiency is the opposite case: when a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy produces enough of a gene product (typically a protein) to bring about a wild-type condition.

The wild-type allele (i.e. version) of a haplosufficient gene is dominant over the mutant allele, since a heterozygote (with one mutant and one normal allele) displays the normal wild-type phenotype (i.e. is not diseased). On the other hand, the wild-type allele of a haploinsufficient gene is recessive to the mutant allele, since a heterozygote (with one mutant and one normal allele) displays the mutant (disease) phenotype. It is also possible that the heterozygote will display a third phenotype (such as diseased but of lesser severity) and in that case, the mutant allele is incompletely dominant to the recessive wild-type allele.

Mechanism

Haploinsufficiency can occur through a number of ways. A mutation in the gene may have erased the production message. One of the two copies of the gene may be missing due to a deletion. The message or protein produced by the cell may be unstable or degraded by the cell.

A haploinsufficient gene is described as needing both alleles to be functional in order to express the wild type. A mutation is not haploinsufficient, but dominant loss of function mutations are the result of mutations in haploinsufficient genes.

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

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.^[1]

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.^[2]

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 elastinis is responsible for supravalvular aortic stenosis, the obstruction in the left ventricular outflow of blood in the heart. ^[3] ^[4]

Human diseases caused by haploinsufficiency

These include:

Some cancers
Cleidocranial dysostosis
Ehlers-Danlos syndrome
Marfan syndrome
Polydactyly
5q- syndrome in myelodysplastic syndrome (MDS)
1q21.1 deletion syndrome
Holt–Oram syndrome
Phelan-McDermid syndrome
Frontotemporal dementia caused by mutations in progranulin

References

Griffiths, Anthony J. et al. (2005). Introduction to Genetic Analysis (8th Ed.). W.H. Freeman. ISBN 0-7167-4939-4
Robinson PN, Arteaga-Solis E, Baldock C, Collod-Béroud G, Booms P, De Paepe A, Dietz HC, Guo G, Handford PA, Judge DP, et al. (2006). "The molecular genetics of Marfan syndrome and related disorders". Journal of Medical Genetics 43:769-787.
Ebert BL, et al. (2008). "Identification of RPS14 as a 5q- syndrome gene by RNA interference screen". Nature 451:335-340.

[1] Lee, J. A. & Lupski, J. R. Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron 52, 103–121 (2006)
[2] Menga, X., Lub, X., Morrisc, C.A. & Keating, M.T. A Novel Human GeneFKBP6Is Deleted in Williams Syndrome*1. Genomics 52, 130- 137 (1998)

^ 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, Berson EL, Dryja TP. 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. 1997 Nov;61(5):1059-66
^ Lee, J. A. & Lupski, J. R. Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders. Neuron 52, 103–121 (2006)
^ Menga, X., Lub, X., Morrisc, C.A. & Keating, M.T. A Novel Human GeneFKBP6Is Deleted in Williams Syndrome*1. Genomics 52, 130- 137 (1998)

UpToDate Contents

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1. 骨髄異形成症候群における細胞遺伝学および分子遺伝学 cytogenetics and molecular genetics of myelodysplastic syndromes
2. 補体系の概要および臨床的評価 overview and clinical assessment of the complement system

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The side population phenomenon enriches for designated adrenocortical progenitor cells in mice.

Lichtenauer U, Shapiro I, Sackmann S, Drouin J, Scheele J, Maneck M, Klein C, Beuschlein F.SourceEndocrine Research Unit, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstraße 1, D-80336 Munich, Germany Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany Laboratoire de Génetique Moléculaire, Institut de Recherches Cliniques de Montréal, Montréal, Quebec, Canada Institut Für Allgemeine Pathologie und Medizinische Klinik I, Universitätsklinikum Freiburg, Freiburg, Germany Experimental Medicine and Therapy Research, University Hospital Regensburg, Regensburg, Germany.
The Journal of endocrinology.J Endocrinol.2012 Dec;215(3):383-391. Epub 2012 Oct 5.
Somatic adrenal stem cells are believed to reside in the periphery of the adrenal cortex throughout life for organ maintenance. Herein, we used the side population (SP) phenomenon to enrich for these progenitors, which made up to 0.01-0.64% of the total cell count. Microarray analysis revealed an ex
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Background-dependent effects of polyglutamine variation in the Arabidopsis thaliana gene ELF3.

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Proceedings of the National Academy of Sciences of the United States of America.Proc Natl Acad Sci U S A.2012 Nov 20;109(47):19363-7. doi: 10.1073/pnas.1211021109. Epub 2012 Nov 5.
Tandem repeats (TRs) have extremely high mutation rates and are often considered to be neutrally evolving DNA. However, in coding regions, TR copy number mutations can significantly affect phenotype and may facilitate rapid adaptation to new environments. In several human genes, TR copy number mutat
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Japanese Journal

Role of the transcription factor Bcl11b in development and lymphomagenesis

KOMINAMI Ryo
Proceedings of the Japan Academy, Series B 88(3), 72-87, 2012
… On the other hand, Bcl11b is a haploinsufficient tumor suppressor and loss of a Bcl11b allele provides susceptibility to mouse thymic lymphoma and human T-cell acute lymphoblastic leukemia. …
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