You have been doing studies on a recessive genetically transmitted disease. You

Question

You have been doing studies on a recessive genetically transmitted disease. You have always suspected that a mutation within the coding region of a specific gene of interest reduces the activity of the protein and therefore causes the disease. You hypothesize this because you can test patient tissue and they seem to have unusually low activity levels of this protein. But, when you sequence both copies of the gene from a patient with the disease you are surprised that there is NOT a mutation in the coding region. So you do total protein isolations from tissue of healthy and diseased patients and when you run them on a SDS-PAGE gel and do a Western blot you find that the diseased patients simply express much less of this protein that healthy ones. Explain three ways this type of recessive disease could be caused without a mutation in a coding region.

Explanation / Answer

The development and function of an organism is in large part controlled by genes. Mutations can lead to changes in the structure of an encoded protein or to a decrease or complete loss in its expression. Because a change in the DNA sequence affects all copies of the encoded protein, mutations can be particularly damaging to a cell or organism. In contrast, any alterations in the sequences of RNA or protein molecules that occur during their synthesis are less serious because many copies of each RNA and protein are synthesized.

Geneticists often distinguish between the genotype and phenotype of an organism. Strictly speaking, the entire set of genes carried by an individual is its genotype, whereas the function and physical appearance of an individual is referred to as its phenotype. However, the two terms commonly are used in a more restricted sense: genotype usually denotes whether an individual carries mutations in a single gene (or a small number of genes), and phenotype denotes the physical and functional consequences of that genotype.

. A recessive mutation is one in which both alleles must be mutant in order for the mutant phenotype to be observed; that is, the individual must be homozygous for the mutant allele to show the mutant phenotype. In contrast, the phenotypic consequences of a dominant mutation are observed in a heterozygous individual carrying one mutant and one normal allele.

For a recessive mutation to give rise to a mutant phenotype in a diploid organism, both alleles must carry the mutation. However, one copy of a dominant mutant allele leads to a mutant phenotype.

Recessive mutations inactivate the affected gene and lead to a loss of function. For instance, recessive mutations may remove part of or all the gene from the chromosome, disrupt expression of the gene, or alter the structure of the encoded protein, thereby altering its function. Conversely, dominant mutations often lead to a gain of function. For example, dominant mutations may increase the activity of a given gene product, confer a new activity on the gene product, or lead to its inappropriate spatial and temporal expression. Dominant mutations, however, may be associated with a loss of function. In some cases, two copies of a gene are required for normal function, so that removing a single copy leads to mutant phenotype. Such genes are referred to as haplo-insufficient. In other cases, mutations in one allele may lead to a structural change in the protein that interferes with the function of the wild-type protein encoded by the other allele. These are referred to as dominant negative mutations.

Some alleles can be associated with both a recessive and a dominant phenotype. For instance, fruit flies heterozygous for the mutant Stubble (Sb) allele have short and stubby body hairs rather than the normal long, slender hairs; the mutant allele is dominant in this case. In contrast, flies homozygous for this allele die during development. Thus the recessive phenotype associated with this allele is lethal, whereas the dominant phenotype is not.

Haploinsufficiency occurs when a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy 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.

Haplosufficiency is the opposite case: when a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy produces enough of a gene product (typically a protein) to bring about a wild-type condition.

The wild-type allele (i.e. version) of a haplosufficient gene is dominant over the mutant allele, since a heterozygote (with one mutant and one normal allele) displays the normal wild-type phenotype (i.e. is not diseased). On the other hand, the wild-type allele of a haploinsufficient gene is recessive to the mutant allele, since a heterozygote (with one mutant and one normal allele) displays the mutant (disease) phenotype. It is also possible that the heterozygote will display a third phenotype (such as diseased but of lesser severity) and in that case, the mutant allele is incompletely dominant to the recessive wild-type allele.

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. These dosage-sensitive genes are vital for human language and constructive cognition.

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

The development and function of an organism is in large part controlled by genes. Mutations can lead to changes in the structure of an encoded protein or to a decrease or complete loss in its expression. Because a change in the DNA sequence affects all copies of the encoded protein, mutations can be particularly damaging to a cell or organism. In contrast, any alterations in the sequences of RNA or protein molecules that occur during their synthesis are less serious because many copies of each RNA and protein are synthesized.

Geneticists often distinguish between the genotype and phenotype of an organism. Strictly speaking, the entire set of genes carried by an individual is its genotype, whereas the function and physical appearance of an individual is referred to as its phenotype. However, the two terms commonly are used in a more restricted sense: genotype usually denotes whether an individual carries mutations in a single gene (or a small number of genes), and phenotype denotes the physical and functional consequences of that genotype.

. A recessive mutation is one in which both alleles must be mutant in order for the mutant phenotype to be observed; that is, the individual must be homozygous for the mutant allele to show the mutant phenotype. In contrast, the phenotypic consequences of a dominant mutation are observed in a heterozygous individual carrying one mutant and one normal allele.

For a recessive mutation to give rise to a mutant phenotype in a diploid organism, both alleles must carry the mutation. However, one copy of a dominant mutant allele leads to a mutant phenotype.

Recessive mutations inactivate the affected gene and lead to a loss of function. For instance, recessive mutations may remove part of or all the gene from the chromosome, disrupt expression of the gene, or alter the structure of the encoded protein, thereby altering its function. Conversely, dominant mutations often lead to a gain of function. For example, dominant mutations may increase the activity of a given gene product, confer a new activity on the gene product, or lead to its inappropriate spatial and temporal expression. Dominant mutations, however, may be associated with a loss of function. In some cases, two copies of a gene are required for normal function, so that removing a single copy leads to mutant phenotype. Such genes are referred to as haplo-insufficient. In other cases, mutations in one allele may lead to a structural change in the protein that interferes with the function of the wild-type protein encoded by the other allele. These are referred to as dominant negative mutations.

Some alleles can be associated with both a recessive and a dominant phenotype. For instance, fruit flies heterozygous for the mutant Stubble (Sb) allele have short and stubby body hairs rather than the normal long, slender hairs; the mutant allele is dominant in this case. In contrast, flies homozygous for this allele die during development. Thus the recessive phenotype associated with this allele is lethal, whereas the dominant phenotype is not.

Haploinsufficiency occurs when a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy 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.

Haplosufficiency is the opposite case: when a diploid organism has only a single functional copy of a gene (with the other copy inactivated by mutation) and the single functional copy produces enough of a gene product (typically a protein) to bring about a wild-type condition.

The wild-type allele (i.e. version) of a haplosufficient gene is dominant over the mutant allele, since a heterozygote (with one mutant and one normal allele) displays the normal wild-type phenotype (i.e. is not diseased). On the other hand, the wild-type allele of a haploinsufficient gene is recessive to the mutant allele, since a heterozygote (with one mutant and one normal allele) displays the mutant (disease) phenotype. It is also possible that the heterozygote will display a third phenotype (such as diseased but of lesser severity) and in that case, the mutant allele is incompletely dominant to the recessive wild-type allele.

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. These dosage-sensitive genes are vital for human language and constructive cognition.

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

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