Haploinsufficiency

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. The genotypic state in which one of two copies of a gene is absent is called hemizygosity. (These terms -- hemizygosity and haploinsufficiency -- are not interchangeable; one describes the genotype, while haploinsufficiency provides a potential mechanism to explain 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, hemizygosity 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.

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
• GLUT1 deficiency (DeVivo syndrome) <Ann Neurol. 2010 Dec;68(6):955-8.>

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)

1. Armanios, M. et al. 2004. Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenital. Genetics. 102(44): 15960–15964.
2. 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
3. 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)
4. Menga, X., Lub, X., Morrisc, C.A. & Keating, M.T. A Novel Human GeneFKBP6Is Deleted in Williams Syndrome*1. Genomics 52, 130- 137 (1998)