Haploinsufficiency is a mechanism of action to explain a phenotype when a diploid organism has lost one copy of a gene and is left with a single functional copy of that gene. Haploinsufficiency is often caused by a loss-of-function mutation, in which having only one copy of the wild-type allele is not sufficient to produce the wild-type phenotype. It occurs when an organism has a single functional copy of a gene, and that single copy does not produce enough product to display the wild type's phenotypic characteristics. The genotypic state in which one of two copies of a gene is absent is called hemizygosity. Hemizygosity is not the same as haploinsufficiency; hemizygosity describes the genotype, and haploinsufficiency is a mechanism that may have caused the phenotype. The general assumption is that the single remaining functional copy of the gene cannot provide sufficient gene product (typically a protein) to preserve the wild-type phenotype leading to an altered or even diseased state. As such, haploinsuffiency is typically transmitted with dominant inheritance, either autosomally or X-linked in female humans.
Dominance describes the circumstance in which both alleles in a diploid organism are present but one allele is responsible for the phenotype. That genotypic state is one of heterozygosity (with two different alleles). Co-Dominance is that situation where the effects of both alleles are apparent in the phenotype.
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. One can not describe a mutation as haploinsufficient; instead, one may describe a gene as being haploinsufficient if a mutation in that gene causes a loss of function and if the loss-of-function phenotype is inherited in a dominant manner relative to the wild-type allele.
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.
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.
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.  
Human diseases caused by haploinsufficiency
- 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) <Ann Neurol. 2010 Dec;68(6):955-8.>
- Haploinsufficiency of A20
- Holoprosencephaly caused by haploinsufficiency for Sonic Hedgehog gene
- Holt–Oram syndrome
- Marfan syndrome
- Phelan–McDermid syndrome
- Dravet Syndrome
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