This type of inheritance indicates the presence of a dominant gene on the X chromosome. Only one copy of the mutated gene is enough to express the trait. Hence, an individual with one X chromosome with a mutated gene expresses the phenotype fully. Unlike X-linked recessive traits, X-linked dominant traits do not necessarily affect males. It equally affects both the sexes. The gene is dominant. Hence, it expresses in the heterozygous females as well as males. Following are the characteristics of the X-linked dominant inheritance:
· All the fathers pass on the trait to all the daughters since it follows an X-linked dominant pattern.
· Sons get affected if the only mother or both the parents get affected with the gene mutation.
· Affected son always has an affected mother.
· Females show a higher prevalence of X-linked dominant disorder since they consist of two copies of the X chromosome.
· The carrier mothers themselves get affected with the disorder. They pass it on to their progeny. 50% of the progeny will get the disorder whereas 50% of the progeny remain unaffected.
· A carrier father will also suffer from the disease apart from transmitting it to the next generation. 100% of his daughters will have the disorder. None of his sons will get affected.
· Consider a case wherein both the parents are carriers. 100% of the daughters will have the disorders. 50% of the sons will have the disorder. The remaining 50% of the sons will be normal.
Image 1: X-linked dominant inheritance (Unaffected father and affected mother)
Image 2: X-linked dominant inheritance (Affected father and unaffected mother)
Following are the examples of X-linked dominant disorders:
Fragile X syndrome:
It is a genetic disorder causing intellectual disability in the children. They have a narrow face, large testis, high arched palate, and difficulty in speaking. Fragile X children are hyperactive. Most of them do not show any physical symptoms before puberty. Sinusitis also occurs among them. They also have anxiety and attention deficit disorder. It occurs due to a mutation in the FMR1 gene. It leads to an increased CGG trinucleotide repeats in the 5’ untranslated region. Unaffected individuals have 20-30 repeats of the CGG trinucleotide. Chromosome Xq27.3 gets methylated. Affected individuals have more than 40 repeats. A constricted region on the X chromosome appears like a fragile site under a microscope. This type of X-linked dominant condition exhibit variable expressivity and reduced penetrance. The FMR1 gene encodes a protein known as FMRP protein. The protein gets involved in synapses and also regulates the production of some other proteins. Abnormally large CGG repeat leads to silencing of FMR1 gene. Loss of FMRP disrupts the functioning of the nervous system.
Rett syndrome:
It is a brain disorder caused due to gene mutations present on the X chromosome. It predominantly affects females. It affects language, coordination, and movements. It affects 1 in 10,000 females between the age of 5 to 18. Such children lose the conscious control of their hands. They also have diminished growth. They lose their ability to walk due to an increased muscle weakness and joint contracture. The infants suffer from poor sucking ability and hypotonia. A gene known as MECP2 is present on the X chromosome. It gets mutated and leads to this condition. It occurs exclusively in girls. Chances of Rett syndrome in boys are quite a few. However, the boys having MECP2 mutation die after birth.
X-linked hypophosphatemia:
It is also known as X-linked vitamin D rickets. It follows X-linked dominant inheritance. A typical feature of X-linked dominant inheritance is bow-leggedness. The symptoms include bone pain, skeletal abnormalities, osteoarthritis, hearing loss, and dental problems. A gene present on the X chromosome known as PHEX gene gets mutated. The PHEX gene regulates the production of a protein known as PHEX protein. The PHEX protein, in turn, regulates another protein known as fibroblast growth factor 23. Parents having a mutated gene pass it on to the next generation. Excessive synthesis of FGF23 reduces the phosphate absorption capacity of the kidneys, leading to hypophosphatemia. The kidneys do not handle vitamin D properly. X-linked hypophosphatemia leads to vitamin D deficiency.
Alport syndrome:
It leads to glomerulonephritis, kidney disease, and hearing loss. It is an X-linked dominant disorder and involves many gene mutations. Mainly, the genes present on the X chromosome get mutated and hence, get passed on from one generation to another. The mode of inheritance of Alport’s syndrome depends on the X chromosome consisting of mutated genes. It either gets inherited from the mother or the father. Certain genes including the COL4A3, COL4A4, and COL4A5 play an important role in the biosynthesis of collagen. Mutations in any of these genes alter its production. Typically, the collagen associated with the glomerulus gets affected. The type IV collagen is important in the basement membrane in the kidneys, lung alveoli, inner ear, and eye. Majority of the mutations occur in COLA5 gene leading to Alport syndrome. In case of more than one gene mutation on the same autosome, it becomes an autosomal recessive disorder.
[1] Medical genetics, G.P. Pal
[2] Human Genetics, 3/e, Gangane
[3] Vogel and Motulsky's Human Genetics: Problems and Approaches, Friedrich Vogel, Gunter Vogel, Arno G. Motulsky
[4] Biology for the IB Diploma: Standard and Higher Level, Andrew Allott
[5] Principles of Medical Genetics, Thomas D. Gelehrter
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