Haploinsufficiency

Last updated April 23, 2023

Haploinsufficiency in genetics describes a model of dominant gene action in diploid organisms, in which a single copy of the wild-type allele at a locus in heterozygous combination with a variant allele is insufficient to produce the wild-type phenotype. Haploinsufficiency may arise from a de novo or inherited loss-of-function mutation in the variant allele, such that it yields little or no gene product (often a protein). Although the other, standard allele still produces the standard amount of product, the total product is insufficient to produce the standard phenotype. This heterozygous genotype may result in a non- or sub-standard, deleterious, and (or) disease phenotype. Haploinsufficiency is the standard explanation for dominant deleterious alleles.^{[ clarification needed ]}

In the alternative case of haplosufficiency, the loss-of-function allele behaves as above, but the single standard allele in the heterozygous genotype produces sufficient gene product to produce the same, standard phenotype as seen in the homozygote. Haplosufficiency accounts for the typical dominance of the "standard" allele over variant alleles, where the phenotypic identity of genotypes heterozygous and homozygous for the allele defines it as dominant, versus a variant phenotype produced only by the genotype homozygous for the alternative allele, which defines it as recessive.

Mechanism

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

Haploinsufficiency in humans

About 3,000 human genes cannot tolerate loss of one of the two alleles.^[1]

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.^[2]

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.^[3]

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.^[4]

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 elastin is responsible for supravalvular aortic stenosis, the obstruction in the left ventricular outflow of blood in the heart.^[5]^[6]

Other examples include:

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) ^[7]
Haploinsufficiency of A20
Holoprosencephaly caused by haploinsufficiency in the Sonic Hedgehog gene
Holt–Oram syndrome
Marfan syndrome ^[8]
Phelan–McDermid syndrome
Polydactyly
Dravet Syndrome
ZTTK
FOXP1 Syndrome
NR4A2-related syndrome

Methods of detection

The most direct method to detect haploinsufficiency is the heterozygous deletion of one allele in a model organism. This can be done in tissue culture cells or in single-celled organisms such as yeast ( Saccharomyces cerevisiae ).^[9]

Related Research Articles

An allele is a variation of the same sequence of nucleotides at the same place on a long DNA molecule, as described in leading textbooks on genetics and evolution.

An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal pairs, which may have different structures. The DNA in autosomes is collectively known as atDNA or auDNA.

<span class="mw-page-title-main">Genetic disorder</span> Health problem caused by one or more abnormalities in the genome

A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders are the most common, the term is mostly used when discussing disorders with a single genetic cause, either in a gene or chromosome. The mutation responsible can occur spontaneously before embryonic development, or it can be inherited from two parents who are carriers of a faulty gene or from a parent with the disorder. When the genetic disorder is inherited from one or both parents, it is also classified as a hereditary disease. Some disorders are caused by a mutation on the X chromosome and have X-linked inheritance. Very few disorders are inherited on the Y chromosome or mitochondrial DNA.

The genotype of an organism is its complete set of genetic material. Genotype can also be used to refer to the alleles or variants an individual carries in a particular gene or genetic location. The number of alleles an individual can have in a specific gene depends on the number of copies of each chromosome found in that species, also referred to as ploidy. In diploid species like humans, two full sets of chromosomes are present, meaning each individual has two alleles for any given gene. If both alleles are the same, the genotype is referred to as homozygous. If the alleles are different, the genotype is referred to as heterozygous.

In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the effect of a different variant of the same gene on the other copy of the chromosome. The first variant is termed dominant and the second recessive. This state of having two different variants of the same gene on each chromosome is originally caused by a mutation in one of the genes, either new or inherited. The terms autosomal dominant or autosomal recessive are used to describe gene variants on non-sex chromosomes (autosomes) and their associated traits, while those on sex chromosomes (allosomes) are termed X-linked dominant, X-linked recessive or Y-linked; these have an inheritance and presentation pattern that depends on the sex of both the parent and the child. Since there is only one copy of the Y chromosome, Y-linked traits cannot be dominant or recessive. Additionally, there are other forms of dominance such as incomplete dominance, in which a gene variant has a partial effect compared to when it is present on both chromosomes, and co-dominance, in which different variants on each chromosome both show their associated traits.

Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. The fruit fly Drosophila melanogaster lacks telomerase, but instead uses retrotransposons to maintain telomeres.

A heterozygote advantage describes the case in which the heterozygous genotype has a higher relative fitness than either the homozygous dominant or homozygous recessive genotype. Loci exhibiting heterozygote advantage are a small minority of loci. The specific case of heterozygote advantage due to a single locus is known as overdominance. Overdominance is a rare condition in genetics where the phenotype of the heterozygote lies outside of the phenotypical range of both homozygote parents, and heterozygous individuals have a higher fitness than homozygous individuals.

In genetics, anticipation is a phenomenon whereby as a genetic disorder is passed on to the next generation, the symptoms of the genetic disorder become apparent at an earlier age with each generation. In most cases, an increase in the severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders, such as Huntington's disease and myotonic dystrophy, where a dynamic mutation in DNA occurs. All of these diseases have neurological symptoms. Prior to the understanding of the genetic mechanism for anticipation, it was debated whether anticipation was a true biological phenomenon or whether the earlier age of diagnosis was related to heightened awareness of disease symptoms within a family.

Equine coat color genetics determine a horse's coat color. Many colors are possible, but all variations are produced by changes in only a few genes. The "base" colors of the horse are determined by the Extension locus, which in recessive form (e) creates a solid chestnut or "red" coat. When dominant (E), a horse is black. The next gene that strongly affects coat color, Agouti, when present on a horse dominant for E, limits the black color to the points, creating a shade known as Bay that is so common and dominant in horses that it is informally grouped as a "base" coat color.

<span class="mw-page-title-main">Human genetics</span> Study of inheritance as it occurs in human beings

Human genetics is the study of inheritance as it occurs in human beings. Human genetics encompasses a variety of overlapping fields including: classical genetics, cytogenetics, molecular genetics, biochemical genetics, genomics, population genetics, developmental genetics, clinical genetics, and genetic counseling.

In genetics, expressivity is the degree to which a phenotype is expressed by individuals having a particular genotype. Expressivity is related to the intensity of a given phenotype; it differs from penetrance, which refers to the proportion of individuals with a particular genotype that actually express the phenotype.

A null allele is a nonfunctional allele caused by a genetic mutation. Such mutations can cause a complete lack of production of the associated gene product or a product that does not function properly; in either case, the allele may be considered nonfunctional. A null allele cannot be distinguished from deletion of the entire locus solely from phenotypic observation.

Dyskeratosis congenita (DKC), also known as Zinsser-Engman-Cole syndrome, is a rare progressive congenital disorder with a highly variable phenotype. The entity was classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa, and MDS/AML, but these components do not always occur. DKC is characterized by short telomeres. Some of the manifestations resemble premature ageing and cognitive impairment can be a feature. The disease initially mainly affects the skin, but a major consequence is progressive bone marrow failure which occurs in over 80%, causing early mortality.

Adams–Oliver syndrome (AOS) is a rare congenital disorder characterized by defects of the scalp and cranium, transverse defects of the limbs, and mottling of the skin.

Hermann J. Muller (1890–1967), who was a 1946 Nobel Prize winner, coined the terms amorph, hypomorph, hypermorph, antimorph and neomorph to classify mutations based on their behaviour in various genetic situations, as well as gene interaction between themselves. These classifications are still widely used in Drosophila genetics to describe mutations. For a more general description of mutations, see mutation, and for a discussion of allele interactions, see dominance relationship.

Telomerase reverse transcriptase is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.

PRP31 pre-mRNA processing factor 31 homolog , also known as PRPF31, is a protein which in humans is encoded by the PRPF31 gene.

Zygosity is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.

<span class="mw-page-title-main">Cancer syndrome</span> Genetic condition that predisposes a person to cancer

A cancer syndrome, or family cancer syndrome, is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancers and may also cause the early onset of these cancers. Cancer syndromes often show not only a high lifetime risk of developing cancer, but also the development of multiple independent primary tumors.

SYNGAP1-related intellectual disability is a monogenetic developmental and epileptic encephalopathy that affects the central nervous system. Symptoms include intellectual disability, epilepsy, autism, sensory processing deficits, hypotonia and unstable gait.

References

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↑ 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; et al. (November 1997). "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. 61 (5): 1059–66. doi:10.1086/301614. PMC 1716046 . PMID 9345108.
↑ Lee, J. A.; Lupski, J. R. (2006). "Genomic rearrangements and gene copy-number alterations as a cause of nervous system disorders". Neuron . 52 (52): 103–121. doi: 10.1016/j.neuron.2006.09.027 . PMID 17015230. S2CID 22412305.
↑ Menga, X.; Lub, X.; Morrisc, C.A.; Keating, M.T. (1998). "A Novel Human GeneFKBP6Is Deleted in Williams Syndrome*1". Genomics . 52 (52): 130–137. doi:10.1006/geno.1998.5412. PMID 9782077.
↑ Rotstein M, Engelstad K, Yang H; et al. (2010). "Glut1 deficiency: inheritance pattern determined by haploinsufficiency". Ann Neurol. 68 (6): 955–8. doi:10.1002/ana.22088. PMC 2994988 . PMID 20687207.{{cite journal}}: CS1 maint: multiple names: authors list (link)
↑ Robinson, P. N.; Arteaga-Solis, E.; Baldock, C.; Collod-Béroud, G.; Booms, P.; De Paepe, A.; Dietz, H. C.; Guo, G.; Handford, P. A.; Judge, D. P.; Kielty, C. M.; Loeys, B.; Milewicz, D. M.; Ney, A.; Ramirez, F. (2006-03-29). "The molecular genetics of Marfan syndrome and related disorders". Journal of Medical Genetics. 43 (10): 769–787. doi:10.1136/jmg.2005.039669. ISSN 1468-6244. PMC 2563177 . PMID 16571647.
↑ Strome, Erin D.; Wu, Xiaowei; Kimmel, Marek; Plon, Sharon E. (March 2008). "Heterozygous screen in Saccharomyces cerevisiae identifies dosage-sensitive genes that affect chromosome stability". Genetics. 178 (3): 1193–1207. doi:10.1534/genetics.107.084103. ISSN 0016-6731. PMC 2278055 . PMID 18245329.