Haploinsufficiency
Encyclopedia
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 a protein
) 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.
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 genes. The hemizygosity of the elastinis is responsible for Aortic Stenosis, the obstruction in the left ventricular outflow of blood in the heart.
(with the other copy inactivated by mutation
) and the single functional copy of the gene produces enough of a gene product
(typically a protein
) to bring about a wild-type condition.
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
) and the single functional copy of the gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
does not produce enough of a gene product (typically a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
) 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
Dominance relationship
Dominance in genetics is a relationship between two variant forms of a single gene, in which one allele masks the effect of the other in influencing some trait. In the simplest case, if a gene exists in two allelic forms , three combinations of alleles are possible: AA, AB, and BB...
, as a heterozygote (with one mutant and one normal allele
Allele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
) displays a phenotypic
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
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
Williams syndrome
Williams syndrome is a rare neurodevelopmental disorder characterized by a distinctive, "elfin" facial appearance, along with a low nasal bridge; an unusually cheerful demeanor and ease with strangers; developmental delay coupled with strong language skills; and cardiovascular problems, such as...
, 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
PRPF31
PRP31 pre-mRNA processing factor 31 homolog , also known as PRPF31, is a protein which in humans is encoded by the PRPF31 gene.- Function :PRPF31 is the gene coding for the splicing factor hPRP31...
, a known cause of autosomal dominant retinitis pigmentosa
Retinitis pigmentosa
Retinitis pigmentosa is a group of genetic eye conditions that leads to incurable blindness. In the progression of symptoms for RP, night blindness generally precedes tunnel vision by years or even decades. Many people with RP do not become legally blind until their 40s or 50s and retain some...
. 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
Non allelic homologous recombination
Non allelic homologous recombination is a form of homologous recombination that occurs between two lengths of DNA that have high sequence homology, but are not alleles....
(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.
Haplosufficiency
Haplosufficiency is the opposite case: when a diploid organism only has a single functional copy of a geneGene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
(with the other copy inactivated by mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
) and the single functional copy of the gene produces enough of a gene product
Gene product
A gene product is the biochemical material, either RNA or protein, resulting from expression of a gene. A measurement of the amount of gene product is sometimes used to infer how active a gene is. Abnormal amounts of gene product can be correlated with disease-causing alleles, such as the...
(typically a protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
) to bring about a wild-type condition.
Human diseases caused by haploinsufficiency
These include:- Some cancerCancerCancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s - Cleidocranial dysostosisCleidocranial dysostosisCleidocranial dysostosis, also called Cleidocranial dysplasia, is a hereditary congenital disorder due to haploinsufficiency caused by mutations in the CBFA1 gene also called Runx2, located on the short arm of chromosome 6....
- Marfan syndromeMarfan syndromeMarfan syndrome is a genetic disorder of the connective tissue. People with Marfan's tend to be unusually tall, with long limbs and long, thin fingers....
- PolydactylyPolydactylyPolydactyly or polydactylism , also known as hyperdactyly, is a congenital physical anomaly in humans, dogs, and cats having supernumerary fingers or toes....
- 5q- syndrome in myelodysplastic syndrome (MDS)Myelodysplastic syndromeThe myelodysplastic syndromes are a diverse collection of hematological medical conditions that involve ineffective production of the myeloid class of blood cells....
- TAR syndromeTAR syndromeTAR Syndrome is a rare genetic disorder that is characterized by the absence of the radius bone in the forearm, and a dramatically reduced platelet count...
, 1q21.1 deletion syndrome1q21.1 deletion syndrome1q21.1 deletion syndrome or 1q21.1 microdeletion is a rare aberration of chromosome 1. , the international rare chromosome disorder group, has 48 genetically confirmed registered cases of this deletion worldwide ....