X LINKED INHERITANCE

X Linked (XL) disorders are encoded on the X chromosome.

Males inherit their X chromosome from their mother, and Y chromosome from their father. So, males don’t have the second X chromosome and they are hemizygote for the genes on X chromosome.

There is a characteristic inheritance pattern of the

phenotypes of the genes on X chromosome.

Almost 500 genes are localized on X chromosome

and 70% of these genes are associated with

disease phenotypes.

In XL inheritance, males can NEVER be carriers. XL disorder manifests in males who are hemizygotes (whatever the disorder is, homozygote or heterozygote).

Males can not inherit their X chromosome from their father, so XL trait NEVER transmits from fathers to sons.

Pedigree shows no male-to-male transmission.

X linked Recessive Inheritance

• Both of the X chromosomes must inherit the disease if a female is affected. If only one X chromosome inherits, then this female is called as a carrier.

• Males can show the symptomes of the disease because of hemizygosity.

Basic Criteria

1- It is more common in males according to females.

2- All daughters of an affected male are obligate carriers

and none of his sons inherit the conditions.

3- 50% of sons from carrier females are affected.

4- There can be carrier females for throughout

generations.

5- Affected males are relatives over females.

6- Heterozygote females are usually not affected, but they

can show the symptomes of the disorders in a varying

degree.

Sex-Linked Recessive Traits An affected son can have parents who have the

normal phenotype. (XAY x XAXa) For a daughter to have the trait, her father must also

have it. Her mother must have it or be a carrier. (XaY, XaXa, XAXa)

The trait often skips a generation from the grandfather to the grandson.

If a woman has the trait (XaXa), all of her sons will be affected.

Pedigrees show only female carriers but no male carriers.

Hemophilia AX x

Maternal

X

YPa

tern

al

normal

XY

Xx

XY

XX

Carrier

affected

1/4 1/4

1/4 1/4

1/2

1/2

F

1/2

1/2

M

Probable patient Patient

xY

- It skips generation- It affects males -- Hemophilia (no factor VIII)

If X linked disease is seen for the first time in a family, then there should be a new mutation, in other words mother is not carrier and the siblings of this child are not affected by this disease.

If a female has a X linked recessive disease, then..a)The karyotype can be 46,XY. But, external genitalia is

female (testicular feminization). b)The karyotype can be 45,XO (Turner syndrome). There is

only one X chromosome, so this female should be affected. c) There can be a translocation between the mutated X

chromosome and autosomal chromosomes. In this situation, translocated X should be active, and the normal X should be inactive.

d)Female should be homozygote for this trait ( mother is carrier and father is affected)

e)Normal X should be inactive and mutated X is active in Lyonization.

LYON HYPOTHESIS(X Inactivation)

One of the X chromosomes in somatic cells of females is active.The second X chromosome is condensed and inactive. This inactive X chromosome is called as “Barr body”.

X inactivation is the process by which dosage compensation of X-linked genes in females is achieved by the transcriptional silencing of one of the two X chromosomes during early development (from day 9 post-fertilization when the inner cell mass of the blastocyst contains 64 cells).

Although there is only one copy or allele

of genes on X chromosome in males and

two copies in females, both of them are

equal in terms of genes.

The mechanism of X inactivation is

DNA methylation.

The genes on the inactive X chromosome are

inactivated by the addition of methyl group to

the cytosines of DNA methyltransferase

enzyme.

The goal of X-inactivation is dosage compensation. The early events in X-inactivation are under the

control of the X chromosome inactivation center (Xic). The XIST (X-inactive specific transcript) gene in the Xic at Xq13.2 is the only gene transcribed exclusively from the inactive X chromosome and is known to play an essential role in the initiation of X-inactivation. XIST gene on the inactive X chromosome is activated by hypermethylation.

Typical Lyonisation

The inactive X chromosome can be either the one that comes from the mother or father. This is chosen randomly and called as “Typical Lyonisation”. But once an X chromosome is inactivated in a cell, then all of the inactivated X chromosomes in this cell line should be the same X chromosome. In other words, inactivation is determined randomly, but it is permanent (irreversible).

Atypical Lyonisation

If one of the X chromosomes has a structural abnormality, this X chromosome is inactivated primarily. In this situation, inactive X is not selected randomly.

If there is a translocation between an autosomal chromosome and X chromosome, the X chromosome that doesn’t have translocation is inactivated.

X inactivation has some important consequences in terms

of clinics and genetics. These are:

dosage compansation

the expression variability in heterozygote females

mosaicism (Mosaicism is the presence of two or more

genetically different cell lines in an individual, all

derived from a single zygote)

There are still some genes that are

expressed in both of the X chromosomes and

escaped from X inactivation.

a) One of the X chromosomes is inactive

b) Randomly inactivation maternal 50% paternal 50%

c) Irreversible inactivation

1961 Mary Lyon

1- It is more common in males according to females. 2- All daughters of an affected male are obligate carriers and non

of his sons inherit the conditions. 3- For a carrier female, 50% of her sons will be affected and 50%

of her daughters will be carriers. 4- The trait is inherited by carrier females. So, the persons who

have the trait are the relatives of the female. 5- Heterozygote females are not affected. The degree to which

females express the disorder is rarely related to X-inactivation patterns.

6- Pedigree shows an oblique pattern. 7- There is no transmission from male to male.

Examples of Sex-Linked Recessive Disorders

Red/Green Colorblindness – Difficulty perceiving differences between colors (red or green, blue or yellow).

Hemophilia – Absence of one or more proteins necessary for normal blood clotting.

Cataracts – opacity in the lens that can lead to blindness Night blindness – (Nyctalopia) rods do not work so that can not see in

the dark Glaucoma – pressure in the eye that can lead to optic nerve damage

and blindness

Duchenne Muscular Dystrophy – progressive weakness and degeneration of skeletal muscles that control movement due to absence of dystrophin (protein that maintains muscle integrity). Mainly in boys, onset 3-5 yrs, by 12 years can’t walk, and later needs respirator.

X Linked Dominant Inheritance

There are also a few genes that have a dominant character on X chromosome and these cause some symptomes in females. The disease can be seen in both males and females. But, the symptomes are more serious in males, sometimes it can be lethal. X linked dominant inherited diseases are very rare. The best known disease is vitamin D resistant rickets.

All children of an affected female has a risk of 50%. Males and females are affected, females usually

less severely affected than males All daughters of affected male are affected but no

male to male transmission. If one of the daughters is not affected or one of the sons is affected , then this shoud be an autosomal inheritance type.

Heterozygote females are also affected

The phenotype of affected females are not as

serious as affected males.

Pedigree pattern is the same as in autosomal

dominant inheritance.

X Linked Dominant Inherited Diseases

X Linked Dominant Inheritance

Vitamin D resistant Rickets Pseudohypoparathyroidism Incontinentia pigmenti

Vitamin D resistant Rickets Phosphate reabsorption by the renal tubules is not normal

hypophosphatemic rickets, vitamin D-resistant rickets

Y Linked Inheritance (Holandric

Inheritance)

Some characters can only be inherited by the genes (holandric genes) on Y chromosome. For example a disease called as ichthyosis hystrix was firstly seen in Lambert family in England in 1710. It was inherited to the other generations in that family, but there was only male to male transmission.

Holandric genes are also responsible from adherent fingers or toes (syndactyly).

1st chromosome has the most genes (2968) and Y chromosome has the least (231).