X-linked genetic disease

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An X-linked genetic disease is a disease inherited through a genetic defect on the X chromosome. In human cells, there is a pair of non-matching sex chromosomes, labelled X and Y. Females carry two X chromosomes, whereas males have one X and one Y chromosome. A disease or trait determined by a gene on the X chromosome demonstrates X-linked inheritance, which can be divided into dominant and recessive patterns.

Contents

The first X-linked genetic disorder described on paper was by John Dalton in 1794, then later in 1910, following Thomas Hunt Morgan's experiment, more about the sex-linked inheritance was understood. In 1961, Mary Lyon proposed the hypothesis of random X-chromosome inactivation providing the fundamental for understanding the mechanism of X-linked inheritance.

There is currently an estimation of 867 X-linked genes identified, with over 533 diseases related to X-linked genes. Common X-linked genetic diseases include Red-green colour blindness, which affects an individual's ability to see red or green images; X-linked agammaglobulinemia, resulting in a deficiency of immunity; Duchenne Muscular Dystrophy, causing muscle weakness and immobility; Hemophilia A, leading to blood clotting deficiency. X-linked recessive diseases are more frequently encountered than dominant ones and predominantly affect males, with Red-green colour blindness having the highest prevalence among all.

Genetic screening including carrier screening, prenatal screening and newborn screening could be done on individuals for early detection of genetic defects. As there are many X-linked genetic diseases, the pathology and mechanism of each varies significantly, there is no clear-cut diagnosis and treatment for all diseases. Methods of diagnosis range from blood tests to genetic tests, while treatments range from specific medications to blood infusion.

History

Red-green colour blindness was the first X-linked genetic disorder described on paper, in 1794 by John Dalton, who is affected by the disorder himself. [1] However, it was not until later that the inheritance pattern and genetics were worked out. The X-chromosome was discovered in 1890 by Hermann Henking, [2] then in 1910, Thomas Hunt Morgan discovered an X-linked mutation on a Drosophila, [3] who then conducted experiments and observations to understand the X-linked inheritance.

In 1961, Mary Lyon proposed that one of the two X chromosomes in female mammalian cells would experience random inactivation (see X-chromosome inactivation) in the early embryonic stage. [4] According to her hypothesis, both males and females should have one single X chromosome that is active. This provided an enhancement for understanding the fundamental mechanisms of X-linked inheritance.

Mode of inheritance

Every human cell consists 23 chromosome pairs, with one of each pair inherited from each parent. 22 of these are homologous chromosomes, meaning they have similar structure and composition. The remaining pair is non-matching sex chromosomes labelled X and Y, which determine the sex of an individual. In humans, females have two X chromosomes while males have one X and one Y.

In each chromosome, there are unique genetic information for different traits encoded by sets of genes found on specific loci. Genes have different versions called alleles, and when an allele is dominant, it can override the effect of the other (recessive). For a dominant trait to be displayed, an individual only requires one dominant allele, whereas expressing a recessive trait requires the possession of two recessive alleles at the same time.

X-linked genetic disorders can arise when there is a spontaneous and permanent change in the DNA sequence of an X-linked gene, known as mutation. Traits or diseases caused by X chromosome genes follow X-linked inheritance, the difference between recessive and dominant inheritance affects the probabilities of an offspring acquiring it from the parents.

X-linked recessive inheritance

X-linked recessive inheritance is coded by the recessive version of a gene. The mutation of a gene on the X chromosome causes the phenotype to be always present in the male, because they have only one X chromosome. The phenotype only occurs in a female if she is homozygous for the mutation. A female with one copy of the mutated gene is considered a carrier.

A carrier female with only one copy of the mutated gene does not often express the diseased phenotype, although X-chromosome inactivation (or skewed X-inactivation), which is common in the female population, may lead to different levels of expression. [5]

In X-linked recessive inheritance, males can only inherit the trait from the mother X-linked recessive (2).svg
In X-linked recessive inheritance, males can only inherit the trait from the mother

There are characteristic patterns for X-linked recessive inheritance. [6] As each parent contributes one sex chromosome to their offspring, sons cannot receive the X-linked trait from affected fathers, who provide only a Y chromosome. Consequently, affected males must inherit the mutated X chromosome from their mothers. X-linked recessive traits are more common in males as they only have one X chromosome, they need only one mutated X chromosome to be affected. In contrast, females have two X chromosomes and must inherit two mutated recessive X alleles, one from each parent, to be affected. X-linked recessive phenotypes tend to skip generations. [7] A grandfather will not affect the son but could affect the grandson by passing the mutated X chromosome to his daughter who is therefore, the carrier.

Common X-linked recessive disorders include Red green colour blindness, Hemophilia A, Duchenne muscular dystrophy.

X-linked dominant inheritance

X-linked dominant traits can affect females as much as males X-linked dominant (affected mother).svg
X-linked dominant traits can affect females as much as males

X-linked dominant inheritance occurs less frequently. Only one copy of the mutated alleles on the X chromosomes is sufficient to cause the disorder when inherited from an affected parent.

Unlike in X-linked recessive inheritance, X-linked dominant traits can affect females as much as males. Affected fathers alone will not lead to affected sons. However, if the mother is also affected, there will be a chance for the sons to be affected depending on which of the X chromosomes (recessive or dominant) is inherited. If a son displays the trait, the mother must also be affected. Some X-linked dominant traits, such as Aicardi syndrome, cause embryonic death in males, leading them to appear only in born females that continue to survive with these conditions.

Examples of X-linked dominant disorders include Rett syndrome, Fragile-X Syndrome, and the most cases in Alport syndrome.

Common X-linked genetic diseases

Red-green colour blindness

Red-green colour blindness is a type of colour vision deficiency (CVD) caused by a mutation in X-linked genes, affecting cone cells responsible for absorbing red or green light.

The perception of red and green light is attributed to the Long (L) wavelength cones and Medium (M) wavelength cones respectively. [8] In Red-green colour blindness, mutations take place on the OPN1LW and OPN1MW genes [9] coding for the photopigments in the cones. In milder cases, those affected exhibit reduced sensitivity to red or green light, as a result of hybridisation of the genes, [9] shifting the response of one cone towards that of the other. [8] In the more extreme conditions, there is a deletion or replacement of the respective coding genes, [10] resulting in the absence of L or M cones photopigments and thus losing the ability to differentiate between red or green light completely.

X-linked agammaglobulinemia

X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder that impairs the body’s ability in producing antibodies, which are proteins protecting us from disease-causing antigens, resulting in severe bacterial infections. [11]

XLA is associated with a mutation in the Bruton's tyrosine kinase (BTK) gene on the X chromosome, [12] which is responsible for producing BTK, an enzyme regulating B cells development. [12] B cells are a type of white blood cells essential in the production of antibodies, when at an early stage, called pre-B cells, they rely on expansion and survival signals involving BTK to mature. [13]

In affected individuals, their BTK genes have an amino acid substitution mutation, [12] altering the amino acid sequence and the structure of BTK making it faulty. Therefore, they have a normal pre-B cell counts but cannot develop mature B cells, resulting in antibody deficiency.

Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is a severe neuromuscular disease causing progressive weakness and damage of muscle tissues, [14] leading to mobility loss and difficulties in daily activities. In a later stage of DMD, as respiratory and cardiac muscles start to degenerate, affected individuals are likely to develop complications such as respiratory failure, cardiomyopathy and heart failure. [14]

DMD arises from a mutation, likely to be the deletion of the exons, [15] [16] a nucleotide sequence in the DMD gene that codes for dystrophin. Dystrophin is a protein responsible for strengthening and stabilising muscle fibres. [17] With the loss of the dystrophin complex, the muscle cells would no longer be protected and therefore result in progressive damage or degeneration.

Haemophilia A

Haemophilia A is a blood clotting disease caused by a genetic defect in clotting factor VIII. It causes significant susceptibility to both internal and external bleeding. Individuals having more severe haemophilia can experience more frequent and intense bleeding.

Severe haemophilia A affects most patients. Patients with mild haemophilia often do not experience heavy bleeding except for surgeries and significant trauma. [18]

Screening

Carrier screening

Carrier screening aims to screen for recessive diseases. Targets of carrier screening typically do not show any symptoms but rather might have a family history of the disease or are in a stage of family planning. Carrier screening is done by performing a blood test on the individual, to identify the specific allele. [19]

Prenatal screening

Prenatal screening is offered to females during pregnancy, it involves both maternal blood tests and ultrasound to check for possible defect genes in developing fetus. [20] The screening result only confirms a possibility of genetic disease, so parents would be prepared psychologically, or could consider the option of pregnancy termination.

Newborn screening

The heel prick test is commonly used. A few drops of blood would be collected with a cotton paper from the heel of a newborn that is less than a week old, [21] samples would then be analysed for a variety of disorders.

See also

Related Research Articles

An allele, or allelomorph, is a variant of the sequence of nucleotides at a particular location, or locus, on a DNA molecule.

<span class="mw-page-title-main">Autosome</span> Any chromosome other than a sex chromosome

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 chromosome 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.

<span class="mw-page-title-main">Heredity</span> Passing of traits to offspring from the species parents or ancestor

Heredity, also called inheritance or biological inheritance, is the passing on of traits from parents to their offspring; either through asexual reproduction or sexual reproduction, the offspring cells or organisms acquire the genetic information of their parents. Through heredity, variations between individuals can accumulate and cause species to evolve by natural selection. The study of heredity in biology is genetics.

<span class="mw-page-title-main">Dominance (genetics)</span> One gene variant masking the effect of another in the other copy of the gene

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 is called 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.

<span class="mw-page-title-main">Oculopharyngeal muscular dystrophy</span> Medical condition

Oculopharyngeal muscular dystrophy (OPMD) is a rare form of muscular dystrophy with symptoms generally starting when an individual is 40 to 50 years old. It can be autosomal dominant neuromuscular disease or autosomal recessive. The most common inheritance of OPMD is autosomal dominant, which means only one copy of the mutated gene needs to be present in each cell. Children of an affected parent have a 50% chance of inheriting the mutant gene.

<span class="mw-page-title-main">X-linked recessive inheritance</span> Mode of inheritance

X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males and in females who are homozygous for the gene mutation, see zygosity. Females with one copy of the mutated gene are carriers.

<span class="mw-page-title-main">Sex linkage</span> Sex-specific patterns of inheritance

Sex linked describes the sex-specific reading patterns of inheritance and presentation when a gene mutation (allele) is present on a sex chromosome (allosome) rather than a non-sex chromosome (autosome). In humans, these are termed X-linked recessive, X-linked dominant and Y-linked. The inheritance and presentation of all three differ depending on the sex of both the parent and the child. This makes them characteristically different from autosomal dominance and recessiveness.

<span class="mw-page-title-main">Non-Mendelian inheritance</span> Type of pattern of inheritance

Non-Mendelian inheritance is any pattern in which traits do not segregate in accordance with Mendel's laws. These laws describe the inheritance of traits linked to single genes on chromosomes in the nucleus. In Mendelian inheritance, each parent contributes one of two possible alleles for a trait. If the genotypes of both parents in a genetic cross are known, Mendel's laws can be used to determine the distribution of phenotypes expected for the population of offspring. There are several situations in which the proportions of phenotypes observed in the progeny do not match the predicted values.

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.

Genetics, a discipline of biology, is the science of heredity and variation in living organisms.

<span class="mw-page-title-main">X-linked dominant inheritance</span> Mode of inheritance

X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome. As an inheritance pattern, it is less common than the X-linked recessive type. In medicine, X-linked dominant inheritance indicates that a gene responsible for a genetic disorder is located on the X chromosome, and only one copy of the allele is sufficient to cause the disorder when inherited from a parent who has the disorder. In this case, someone who expresses an X-linked dominant allele will exhibit the disorder and be considered affected. The pattern of inheritance is sometimes called criss-cross inheritance.

<span class="mw-page-title-main">Labrador Retriever coat colour genetics</span> Genetics behind Labrador Retriever coat colour

The genetic basis of coat colour in the Labrador Retriever has been found to depend on several distinct genes. The interplay among these genes is used as an example of epistasis.

Pseudodominance is the situation in which the inheritance of a recessive trait mimics a dominant pattern.

<span class="mw-page-title-main">Hereditary carrier</span> Organism with a recessive genetic allele that does not display the recessive trait

A hereditary carrier, is a person or other organism that has inherited a recessive allele for a genetic trait or mutation but usually does not display that trait or show symptoms of the disease. Carriers are, however, able to pass the allele onto their offspring, who may then express the genetic trait.

An obligate carrier is an individual who may be clinically unaffected but who must carry a gene mutation based on analysis of the family history; usually applies to disorders inherited in an autosomal recessive and X-linked recessive manner.

Glycerol kinase deficiency (GKD) is an X-linked recessive enzyme defect that is heterozygous in nature. Three clinically distinct forms of this deficiency have been proposed, namely infantile, juvenile, and adult. National Institutes of Health and its Office of Rare Diseases Research branch classifies GKD as a rare disease, known to affect fewer than 200,000 individuals in the United States. The responsible gene lies in a region containing genes in which deletions can cause Duchenne muscular dystrophy and adrenal hypoplasia congenita. Combinations of these three genetic defects including GKD are addressed medically as Complex GKD.

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

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

This glossary of genetics and evolutionary biology is a list of definitions of terms and concepts used in the study of genetics and evolutionary biology, as well as sub-disciplines and related fields, with an emphasis on classical genetics, quantitative genetics, population biology, phylogenetics, speciation, and systematics. It has been designed as a companion to Glossary of cellular and molecular biology, which contains many overlapping and related terms; other related glossaries include Glossary of biology and Glossary of ecology.

References

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  2. ↑ Schwartz, James (2009). In pursuit of the gene: from Darwin to DNA (1. paperback ed.). Cambridge, Mass.: Harvard Univ. Press. ISBN   978-0-674-03491-4.
  3. ↑ Green, M M (2010-01-01). "2010: A Century of Drosophila Genetics Through the Prism of the white Gene". Genetics. 184 (1): 3–7. doi:10.1534/genetics.109.110015. ISSN   1943-2631. PMC   2815926 . PMID   20061564.
  4. ↑ DISTECHE, CHRISTINE M.; BERLETCH, JOEL B. (2015-12-01). "X-chromosome inactivation and escape". Journal of Genetics. 94 (4): 591–599. doi:10.1007/s12041-015-0574-1. ISSN   0973-7731. PMC   4826282 . PMID   26690513.
  5. ↑ Shvetsova, Ekaterina; Sofronova, Alina; Monajemi, Ramin; Gagalova, Kristina; Draisma, Harmen H. M.; White, Stefan J.; Santen, Gijs W. E.; Chuva de Sousa Lopes, Susana M.; Heijmans, Bastiaan T.; van Meurs, Joyce; Jansen, Rick; Franke, Lude; Kiełbasa, Szymon M.; den Dunnen, Johan T.; ‘t Hoen, Peter A. C. (2018-12-14). "Skewed X-inactivation is common in the general female population". European Journal of Human Genetics. 27 (3): 455–465. doi:10.1038/s41431-018-0291-3. ISSN   1018-4813. PMC   6460563 . PMID   30552425.
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  9. 1 2 Deeb, Samir S (2004-07-01). "Molecular genetics of colour vision deficiencies". Clinical and Experimental Optometry. 87 (4–5): 224–229. doi:10.1111/j.1444-0938.2004.tb05052.x. ISSN   0816-4622. PMID   15312026.
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  11. ↑ Smith, C. E.; Berglöf, A. (1993), Adam, M. P.; Feldman, J.; Mirzaa, G. M.; Pagon, R. A. (eds.), "X-Linked Agammaglobulinemia", GeneReviews®, Seattle (WA): University of Washington, Seattle, PMID   20301626 , retrieved 2024-03-27
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  14. 1 2 Venugopal, Vijay; Pavlakis, Steven (2024), "Duchenne Muscular Dystrophy", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID   29493971 , retrieved 2024-03-27
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  19. ↑ Antonarakis, Stylianos E. (September 2019). "Carrier screening for recessive disorders". Nature Reviews Genetics. 20 (9): 549–561. doi:10.1038/s41576-019-0134-2. ISSN   1471-0056. PMID   31142809.
  20. ↑ Cuckle, Howard; Maymon, Ron (2016-02-01). "Development of prenatal screening—A historical overview". Seminars in Perinatology. The Changing Paradigm of Perinatal screening for Birth Defects. 40 (1): 12–22. doi:10.1053/j.semperi.2015.11.003. ISSN   0146-0005. PMID   26764253.
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