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 expressed (1) in males (who are necessarily hemizygous for the gene mutation because they have only one X chromosome) and (2) in females who are homozygous for the gene mutation (i.e., they have a copy of the gene mutation on each of their two X chromosomes). X-linked inheritance means that the gene causing the trait or the disorder is located on the X chromosome. Females have two X chromosomes, while males have one X and one Y chromosome. Carrier females who have only one copy of the mutation do not usually express the phenotype, although differences in X chromosome inactivation can lead to varying degrees of clinical expression in carrier females since some cells will express one X allele and some will express the other. The current estimate of sequenced X-linked genes is 499 and the total including vaguely defined traits is 983[1] [edit] Sex Differences In Phenotype/Genotypes and Frequency In humans, generally "men are affected and women are carriers" for two reasons. The first is the simple statistical fact that if the X-chromosomes is a population that carry a particular X-linked mutation at a frequency of 'f' (for example, 1%) then that will be the frequency that men are likely to express the mutation (since thay have only one X), while women will express it at a frequency of f2 (for example 1% * 1% = 0.01%) since they have two X's and hence two chances to get the normal allele. Thus, X-linked mutations tend to be rare in women. The second reason for female rarity is that women who express the mutation must have two X chromosomes that carry the trait and they necessarily got one from their father, who would have also expressed the trait because he only had one X chromosome in the first place. If the trait lowers the probability of fathering a child or induces the father to only have children with women who aren't carriers (so as not to create daughters who are carriers rather than expressers and then only if no genetic screening is used) then women become even less likely to express the trait than the statistical prediction of f2 . [edit] Examples There are approximately 290[2] traits or diagnoses known or suspected to be X-linked (at least in some forms of the diagnosis).
[edit] Most common The most common X-linked recessive disorders are:[2] - Red-Green color blindness; a classic example of an X-linked trait because it is easy to explain the phenotype and it's relatively common [3] (7% to 10% of men are carriers making the above calculations predict 0.49% to 1% for women). Its commonness may be attributable to its not being a serious disability in most cases and an actual advantage in some situations (for example, not being distracted by some of the color in color based camouflage).It is also known as daltonism.
- Hemophilia A; another famous example because it was found in European royal families who intermarried and were famous enough that their pedigrees could be established and offered in textbooks as a "famous example" of an X-linked trait that had been documented in history books before mendelian genetics was understood.
- Fragile X syndrome; resulting in a spectrum of characteristic physical, intellectual, emotional and behavioural features which range from severe to mild in manifestation. The syndrome is associated with the expansion of a single trinucleotide gene sequence (CGG) on the X chromosome, and results in a failure to express the FMR-1 protein which is required for normal neural development.
- Duchenne muscular dystrophy; muscular dystrophy associated with mutations in the dystrophin gene, characterized by rapid progression of muscle degeneration, eventually leading to loss in ambulation, respiratory failure and death.
- Becker's muscular dystrophy; milder form of Duchenne, causes slowly progressive muscle weakness of the legs and pelvis.
- Hemophilia B; a blood clotting disorder caused by a mutation of the Factor IX gene, leading to a deficiency of Factor IX. It is rarer than haemophilia A. It's also called Christmas disease
- X-linked ichthyosis; a skin condition (ichthyosis) caused by the hereditary deficiency of the steroid sulfatase (STS) enzyme that affects 1 in 2000 to 1 in 6000 males.[4]
- X-linked agammaglobulinemia (XLA); affects the body's ability to fight infection (origin of the name: A=no, gammaglobulin=Antibody). XLA patients do not generate mature B cells.[5] B cells are part of the immune system and normally manufacture antibodies (also called immunoglobulins) which defends the body from infections (the humoral response). Patients with untreated XLA are prone to develop serious and even fatal infections.[6]
- Glucose-6-phosphate dehydrogenase deficiency; may exhibit nonimmune hemolytic anemia in response to a number of causes, most commonly infection or exposure to certain medications or chemicals.
[edit] Less common disorders Theoretically, a mutation in any of the genes in the Category:Genes on chromosome X may cause disease, but below are some notable ones, with short description of symptoms: - Adrenoleukodystrophy; leads to progressive brain damage, failure of the adrenal glands and eventually death.
- Alport syndrome; glomerulonephritis, endstage kidney disease, and hearing loss.
- Androgen insensitivity syndrome; variable degrees of undervirilization and/or infertility in XY persons of either gender
- Barth syndrome; metabolism distortion, delayed motor skills, stamina deficiency, hypotonia, chronic fatigue, delayed growth, cardiomyopathy, and compromised immune system.
- Centronuclear myopathy; where cell nuclei are abnormally located in skeletal muscle cells. In CNM the nuclei are located at a position in the center of the cell, instead of their normal location at the periphery.
- Charcot-Marie-Tooth disease (CMTX2-3); disorder of nerves (neuropathy) that is characterized by loss of muscle tissue and touch sensation, predominantly in the feet and legs but also in the hands and arms in the advanced stages of disease.
- Coffin-Lowry syndrome; severe mental retardation sometimes associated with abnormalities of growth, cardiac abnormalities, kyphoscoliosis as well as auditory and visual abnormalities.
- Fabry disease; A lysosomal storage disease causing anhidrosis, fatigue, angiokeratomas, burning extremity pain and ocular involvement.
- Hunter's Syndrome; potentially causing hearing loss, thickening of the heart valves leading to a decline in cardiac function, obstructive airway disease, sleep apnea, and enlargement of the liver and spleen.
- Hypohidrotic ectodermal dysplasia, presenting with hypohidrosis, hypotrichosis, hypodontia
- Kabuki syndrome; multiple congenital anomalies and mental retardation.
- Kennedy disease; muscle cramps and progressive weakness
- Lesch-Nyhan syndrome; neurologic dysfunction, cognitive and behavioral disturbances including self-mutilation, and uric acid overproduction (hyperuricemia)
- Lowe Syndrome; hydrophthalmia, cataracts, intellectual disabilities, aminoaciduria, reduced renal ammonia production and vitamin D-resistant rickets
- Menkes disease; sparse and coarse hair, growth failure, and deterioration of the nervous system
- Nonsyndromic deafness and X-linked nonsyndromic deafness; hearing loss
- Norrie disease; cataracts, leukocoria along with other developmental issues in the eye
- Occipital horn syndrome; deformations in the skeleton
- Ornithine transcarbamylase deficiency; developmental delay and mental retardation. Progressive liver damage, skin lesions, and brittle hair may also be seen
- Siderius X-linked mental retardation syndrome; cleft lip and palate with mental retardation and facial dysmorphism, caused by mutations in the histone demethylase PHF8
- Simpson-Golabi-Behmel syndrome; coarse faces with protruding jaw and tongue, widened nasal bridge, and upturned nasal tip
- Spinal muscular atrophy caused by UBE1 gene mutation; weakness due to loss of the motor neurons of the spinal cord and brainstem
- Wiskott-Aldrich syndrome; eczema, thrombocytopenia, immune deficiency, and bloody diarrhea
- X-linked Severe Combined Immunodeficiency (SCID); infections, usually causing death in the first years of life
- X-linked sideroblastic anemia; skin paleness, fatigue, dizziness and enlarged spleen and liver.
[edit] See also [edit] External links [edit] References |
