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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.

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

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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

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Every human cell consists of 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 labeled 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 is 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 probability of an offspring acquiring it from the parents.

X-linked recessive inheritance

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In X-linked recessive inheritance, males can only inherit the trait from the mother

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] 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

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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 who 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

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Red-green colour blindness

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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

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X-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder that impairs the body’s ability to produce 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

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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

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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

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Carrier screening

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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

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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

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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

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References

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  1. ^ Hunt, David M.; Dulai, Kanwaijit S.; Bowmaker, James K.; Mollon, John D. (1995-02-17). "The Chemistry of John Dalton's Color Blindness". Science. 267 (5200): 984–988. Bibcode:1995Sci...267..984H. doi:10.1126/science.7863342. ISSN 0036-8075. PMID 7863342.
  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.
  6. ^ Alliance, Genetic; Screening Services, The New York-Mid-Atlantic Consortium for Genetic and Newborn (2009-07-08), "INHERITANCE PATTERNS", Understanding Genetics: A New York, Mid-Atlantic Guide for Patients and Health Professionals, Genetic Alliance, retrieved 2024-03-27
  7. ^ Pierce, Benjamin A. (2020). Genetics: A Conceptual Approach. Macmillan Learning. pp. 154–155. ISBN 978-1-319-29714-5.
  8. ^ a b Barton, Jason J. S.; Leff, Alexander; Aminoff, Michael J.; Boller, François; Swaab, D. F., eds. (2021). "Colour Vision". Neurology of vision and visual disorders. Handbook of clinical neurology. 3rd series. Vol. 178. Amsterdam, Netherlands: Elsevier. pp. 133–141. ISBN 978-0-12-821377-3. OCLC 1237102002.
  9. ^ a b 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.
  10. ^ Neitz, J.; Neitz, M. (2011). "The genetics of normal and defective color vision". Vision Research. 51 (7): 633–651. doi:10.1016/j.visres.2010.12.002. PMC 3075382. PMID 21167193.
  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
  12. ^ a b c Maas, A.; Hendriks, R. W. (2001). "Role of Bruton's tyrosine kinase in B cell development". Developmental Immunology. 8 (3–4): 171–181. doi:10.1155/2001/28962. PMC 2276078. PMID 11785667.
  13. ^ McDonald, C.; Xanthopoulos, C.; Kostareli, E. (2021). "The role of Bruton's tyrosine kinase in the immune system and disease". Immunology. 164 (4): 722–736. doi:10.1111/imm.13416. ISSN 0019-2805. PMC 8561098. PMID 34534359.
  14. ^ a b Venugopal, Vijay; Pavlakis, Steven (2024), "Duchenne Muscular Dystrophy", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 29493971, retrieved 2024-03-27
  15. ^ Yiu, Eppie M; Kornberg, Andrew J (August 2015). "Duchenne muscular dystrophy". Journal of Paediatrics and Child Health. 51 (8): 759–764. doi:10.1111/jpc.12868. ISSN 1034-4810. PMID 25752877.
  16. ^ Aartsma-Rus, Annemieke; Ginjaar, Ieke B; Bushby, Kate (March 2016). "The importance of genetic diagnosis for Duchenne muscular dystrophy". Journal of Medical Genetics. 53 (3): 145–151. doi:10.1136/jmedgenet-2015-103387. ISSN 0022-2593. PMC 4789806. PMID 26754139.
  17. ^ Gao, Q. Q.; McNally, E. M. (2011-01-17). Terjung, Ronald (ed.). Comprehensive Physiology. Vol. 5 (1 ed.). Wiley. pp. 1223–1239. doi:10.1002/cphy.c140048. ISBN 978-0-470-65071-4. PMC 4767260. PMID 26140716.
  18. ^ Konkle, Barbara A.; Nakaya Fletcher, Shelley (1993). "Hemophilia A". GeneReviews®. Seattle (WA): University of Washington, Seattle. PMID 20301578.
  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.
  21. ^ Anderson, R.; Rothwell, E.; Botkin, J. R. (2011). "Newborn Screening". Annual Review of Nursing Research. 29 (1): 113–132. doi:10.1891/0739-6686.29.113. ISSN 0739-6686. PMC 7768912. PMID 22891501.
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