X-linked dominant inheritance

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.

References:
[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

© Copyright, 2018 All Rights Reserved.

X-linked recessive inheritance

The recessive mutant allele is present on the X chromosome. Some of the genes present on the X chromosome functionally resemble the genes present on the autosomes. The recessive traits manifest only in a homozygous state or in a double dose. A mutation of a gene present on the X chromosome expresses the phenotype in males. These males show hemizygosity for the gene mutation since they have only one X chromosome. The females show homozygosity for the gene mutation. Since the females have two X chromosomes, they have a copy of the gene mutation on each X chromosome. Carriers have only one copy of the mutant gene. Hence, they do not express the phenotype. A carrier female transmits the gene to the next generation. An affected male transmits the mutant gene to all his daughters who become carriers in the future.

Characteristics:

1.     The X-linked recessive inheritance predominantly affects males since they consist of a single X chromosome with the affected or a mutated gene.

2.     A homozygous female is rare in this case (mutant allele occurs mostly in the double dose).

3.     Mostly, the unaffected carrier females transmit the mutant gene to their sons.

Consider a mating between a normal male and a carrier female. 25% of the females exhibit a normal phenotype, 25% of the males exhibit a normal phenotype, 25% of the females become carriers, and remaining 25% of the males exhibit a normal phenotype. Consider another mating example between the affected male and a normal female. In this case, an affected male will never transmit the disorder. 50% of the females will become carriers whereas 50% of the males will exhibit a normal phenotype.

 Image 1: X-linked recessive inheritance (Affected father and unaffected mother)

                        Image 2: X-linked recessive inheritance (Unaffected father and carrier mother)

Disorders associated with X-linked recessive inheritance:

Duchenne muscular dystrophy (DMD):

It severely affects the muscles. This type of dystrophinopathy is predominant in males. DMD involves severe muscular weakness and wasting. An affected person shows an awkward structure of the shoulders and arms while walking. They have very weak belly muscles. These weak muscles lead to the sticking of the belly, thereby affecting the sitting position of the person. Individuals with DMD have weak thighs, weak muscles in the front leg, foot drop and bent knees. Children with DMD may walk on toes due to tight heel cord (contracture). The calf muscles get replaced by fat and the connective tissues. Most of them use a wheelchair since they show difficulty in walking. A gene known as DMD gene gets mutated. The DMD gene encodes a protein known as dystrophin. Different kinds of DMD gene mutations exist. They lead to a wide range of dystrophinopathies. The protein dystrophin mainly gets synthesized in the heart and the skeletal muscles. However, neurons also synthesize this protein in small amounts. Inheritance of DMD follows an X-linked recessive pattern of inheritance. Improper synthesis of dystrophin protein due to DMD gene mutation affects the muscles and the bones of the individual. In DMD, the dystrophin is almost not there. Hence, muscle cells become a deficit of this essential protein. Muscle cells start becoming weak and hence, they die. Patients with DMD also experience heart problems.

Mainly the X chromosome consists of the DMD gene. Hence, a mutated DMD gene mainly passes through the X chromosome. Males have only one X chromosome. Females have two X chromosomes. Each X chromosome has a single copy of the DMD gene. Males receive their X chromosome from the mother and Y chromosome from the father. Hence, the mutated gene passes on from the mother. Since females have two X chromosomes, so they get the disorder if both the X chromosomes have a mutated gene. If one X chromosome has a mutated gene, the females become carriers of DMD gene mutation. A man with DMD will pass on the trait to all his daughters. Since sons inherit Y chromosome, the father may not pass the trait to the son. Sometimes de novo mutations also occur in the family.

Hemophilia:

It belongs to a category of bleeding disorders. It lowers the body’s natural process of blood clotting. Individuals with hemophilia bleed for a very long time. Bleeding in these individuals not necessarily involve an accident or an injury. It may also happen spontaneously. Individuals suffering from hemophilia have blood in their urine and the stools. Their gums always bleed. They also have deep bruises, frequent nosebleeds, and joint pains.

There are two main types of hemophilia. Hemophilia A (classic hemophilia) results in factor VIII protein deficiency thereby affecting 1 in 4000 individuals. Hemophilia B (Christmas disease) arises due to factor IX protein deficiency and affects 1 in 20,000 individuals. Hemophilia occurs commonly in males than in females.

Genetics:

Hemophilia A arises due to changes in a gene known as F8 gene. A normal F8 gene provides instructions in making coagulation factor VIII protein. Hemophilia B arises due to changes in the F9 gene. It encodes coagulation factor IX. Both the proteins work together in the blood clotting process. A blood clot majorly plays a role in protecting the body from excessive blood loss. Without the factor VIII and factor IX proteins, the blood clotting process becomes inefficient.

The genes associated with hemophilia are present on the X chromosome. Males have one copy of X chromosome inherited from the mother. Hence, if the mother has a copy of a mutated gene on the X chromosomes, she becomes a carrier of the trait. Females have two X chromosomes. Hence, they either become carriers or express the trait fully.

Color blindness:

Color blindness (an X-linked recessive type of disorder) is responsible for lowering a person’s ability to see colors or differentiate color shades. These individuals face a problem in identifying colors and hence, get confused while performing tasks. Identifying traffic lights, selecting ripe fruits, and identifying next to similar colors becomes difficult for them. They become uncomfortable in bright environments. Such individuals have a problem in the development of the color sensing cones in the eye. Color blindness gets detected using the Ishihara test of determining various colors. There are many forms of color blindness such as red-green color blindness, blue-yellow color blindness, and total color blindness.

Genetics:

The X chromosomal genes such as OPN1LW, OPN1MW, and OPN1SW get mutated leading to color vision deficiency. A light-sensitive tissue consists of the color vision promoting proteins. It is present at the backside of the eye. The ophthalmic structures (consisting of rods and cones) transmit the signals from the eye to the brain. Rods provide vision in low light whereas cones provide vision in bright light. The above genes help in making opsins in the cones. Mutated genes result in color blindness or difficulty in visualizing specific spectrum of colors. 

References:
[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

© Copyright, 2018 All Rights Reserved.