The haploinsufficiency is a carrier in which an individual of a single dominant allele expresses an abnormal phenotype uncharacteristic of that trait genetic phenomenon. It is therefore an exception to the classic dominance / recessivity relationships.
In a way it is different from incomplete dominance, since the haploinsufficient also does not manifest the trait as intermediate between the extremes of the character. Haploinsufficiency results from altered or insufficient expression of the product encoded by the solitary functional allele.
It is, then, an allelic condition that can affect both heterozygotes and hemizygotes in diploid individuals. It is a medical term to define certain genetic-based conditions, almost always metabolic. It is, to some extent, incomplete dominance with clinical consequences.
All humans are hemizygous for genes on the sex chromosome pair. Men, because they carry a single X chromosome, in addition to a Y chromosome that is not homologous to the previous one.
Women, because even when they carry two copies of the X chromosome, only one is functional in each cell of the body. The other is inactivated by gene silencing, and therefore generally genetically inert.
However, humans are not haploinsufficient for all the genes carried by the X chromosome. Another way to be hemizygous (non-sexual) for a particular gene is to possess a particular allele at the specific locus on a chromosome, and a deletion of it in the homologous pair.
Haploinsufficiency is not a mutation. However, a mutation in the gene of interest affects phenotypic behavior in a haploinsufficient heterozygous, since the single functional allele of the gene is not sufficient to determine the normality of its carrier. Haploinsufficiencies are generally pleiotropic.
Haploinsufficiency in heterozygotes
Monogenic traits are determined by the expression of a single gene. These are the typical cases of allelic interaction, which depending on the genetic makeup of the individual, will have a unique manifestation - almost always of all or nothing.
That is, homozygous dominant (AA) and heterozygous (Aa) will display the wild-type (or "normal") phenotype, while homozygous recessive (aa) will display the mutant phenotype. This is what we call a dominant allelic interaction.
When dominance is incomplete, the heterozygous trait is intermediate as a consequence of a decreased genetic dosage. In haploinsufficient heterozygotes, such poor dosing does not allow the function that the gene product should fulfill in a normal way.
This individual will show the phenotype of his heterozygosity for this gene as a disease. Many autosomal dominant diseases meet this criteria, but not all.
That is, the dominant homozygous will be healthy, but individuals with any other genetic makeup will not. In the homozygous dominant, normality will be the health of the individual; in the heterozygous, the manifestation of the disease will be dominant.
This apparent contradiction is simply a consequence of the deleterious (clinical) effect in the individual of a gene that is not expressed at adequate levels.
Haploinsufficiency in hemizygotes
The situation changes (from the genotype point of view) in hemizygotes since we speak of the presence of a single allele for the gene. That is, as if it were a partial haploid for that locus or group of loci.
This can occur, as we already mentioned, in carriers of deletions or in carriers of dimorphic sex chromosomes. However, the effect of the decreased dosage is the same.
There may, however, be slightly more complicated cases. For example, in Turner syndrome presented by women with a single X chromosome (45, XO), the disease appears to be due not to the hemizygous phenotypic condition of the X chromosome.
Rather, haploinsufficiency here is due to the presence of a few genes that normally behave as pseudoautosomal. One of these genes is the SHOX gene, which normally escapes inactivation by silencing in women.
It is also one of the few genes shared by the X and Y chromosomes. That is, it is normally a "diploid" gene in both women and men.
The presence of a mutant allele in this gene in heterozygous females, or a deletion (absence) of it in a female will be responsible for SHOX haploinsufficiency. One of the clinical manifestations of the haploinsufficient condition for this gene is short stature.
Causes and effects
In order to fulfill its physiological roles, a protein with enzymatic activity must reach at least a threshold of action that meets the needs of the cell, or the organism. Otherwise, it will give rise to a deficiency.
A simple example of a poor metabolic threshold with dramatically pleiotropic consequences is that of telomerase haploinsufficiency.
Without the combined action of the expression of the two alleles of the gene that encodes it, the decrease in telomerase levels results in an alteration in the control of telomere length. This generally manifests as degenerative disorders in the affected individual.
Action of telomerase on telomere shortening. Fatma Uzbas (Spanish version by Alejandro Porto), via Wikimedia Commons
Other proteins that are not enzymes can give rise to a deficiency because, for example, they are not sufficient to fulfill a structural role within the cell.
Ribosomal diseases in humans, for example, comprise a series of disorders that are mainly caused by alterations in ribosome biogenesis or by haploinsufficiency.
In the latter case, a decrease in the normal levels of availability of ribosomal proteins leads to a global alteration in protein synthesis. The phenotypic manifestation of this marked dysfunction will depend on the type of tissue or cell affected.
In other cases, haploinsufficiency is caused by low levels of proteins that are unable to contribute to the activation of others. This distortion due to inadequate dosage can therefore lead to a deficient metabolic condition, a structural deficiency that affects other functions, or the absence of expression of other genes or of the activity of their products.
This would largely explain the pleiotropic manifestations in clinical syndromes that are characteristic of haploinsufficiency.
The SHOX gene product, despite the complications derived from its residence in a complex chromosomal pair, is a good example of this. The SHOX gene is a homeotic gene, which is why its deficiency directly affects the normal morphological development of the individual.
Other haploinsufficiencies may derive from chromosomal rearrangements of the carrier region of the affected gene, which without mutation or deletion, affect or cancel the expression levels of the modified allele.
References
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