Haploinsufficiency occurs when a diploid organism only has a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy of the gene does not produce enough of a gene product (typically aprotein) 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.
Haploinsufficiency is therefore an example of incomplete or partial dominance, as a heterozygote (with one mutant and one normal allele) displays a phenotypic effect.
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 genes. The hemizygosity of the elastinis is responsible for Aortic Stenosis, the obstruction in the left ventricular outflow of blood in the heart.