By,

Juthika Acharjee
Roll.: 061614 No.: 02014765
Registration No.: 01-140060597
6th Semester, Zoology Honours
Gurucharan College, Silchar
Contents:
 The X-chromosome & X-linked diseases

 Types of X-linked diseases.

 Inheritance patterns of dominant & recessive X-linked

diseases.

 Symptoms & genetics of some X-linked diseases.

 Pedigree analysis of different types of X-linked diseases

 References
THE X-CHROMOSOME & X-LINKED TRAITS
 X-Linked Diseases are of two types :
A. X-Linked Dominant Diseases :
• Refers to situations where a single dominant allele on the X
chromosome can lead to a trait/condition.
• Twice as many females are affected as males.
• Usually half the children of an affected female will be affected,
regardless of sex.
• All the daughters of an affected male will be affected but none of the
sons.
B. X-Linked Recessive Diseases :
• Refers to those situations where one recessive allele on the X
chromosome cannot lead to a trait/condition or disorder.
• Males are affected more often than females.
• Ratio of 8:1.
• Affected males will transmit the allele to all daughters, but not to sons.
• Homozygous recessive females arise only from matings in which the
father is affected & the mother is either affected or a carrier.
Some Examples Of Dominant X-linked
Diseases:
1. Vitamin-D resistant Rickets
2. Fragile X Syndrome
Some Examples Of Recessive X-linked
Diseases:
1. Haemophillia
2. Colourblindness.
 Inheritance pattern of Dominant X-linked Diseases:
Here a single dominant allele on the X chromosome can lead to a trait/condition.
Each child of a mother affected with a dominant X-linked trait has a 50% chance of
inheriting the mutation irrespective of the sex & thus being affected with the disorder.
If only the father is affected 100% of daughters will be affected while none of the
sons will be affected.
 Inheritance pattern of Recessive X-linked Diseases:
Here a recessive allele on the X chromosome can not lead to a trait/condition or
disorder.
Female carriers do not manifest the clinical symptoms of the disorder.
All males possessing a mutant X-chromosome will be affected since they have only one
X-chromosome .
All offsprings of a carrier mother have a 25% chance of inheriting the mutation if
the father is unaffected. If the mother is unaffected, then all the daughters of an
affected father will be carriers while no sons will be affected.
Father Mother Father Mother
is is is is
normal carrier affected normal
 VITAMIN D-RESISTANT RICKETS

• X-linked Hypophosphatemia
(XLH), or X-linked Vitamin-D
resistant rickets differs from most
cases of rickets as Ingestion of
vitamin-D is relatively ineffective.
 Prominent symptoms include :
 bone deformities including
short stature & genu varum
(bow leggedness).
 Bone pain
 Osteoarthritis
 Hearing loss(less common).

Fig: X-ray images of skeletal abnormality in a patients

of XLH.
GENETICS:
Mutation in the PHEX gene sequence &
subsequent inactivity of PHEX protein.

PHEX protein regulates another protein

called fibroblast growth factor 23
(produced from FGF 23 gene).

FGF23 inhibits kidneys’ ability to reabsorb

phosphate into the bloodstream.

Resulting over-activity of FGF-23 reduces

Vitamin-D 1α-hydroxylation & phosphate
reabsorption by the kidneys leading to
Hypophosphatemia.
 FRAGILE-X SYNDROME
 Inherited genetic disorder
causing intellectual &
developmental disabilities.
 The most prominent physical
symptoms include—
 Large protruding ears & Long Fig: facial features
face (vertical maxillary excess)
 Hyper-extensible finger joints &
thumbs
 Post-pubescent macro-orchidism
(enlargement of testicles in men
after puberty)
Fig: The FXS gene
GENETICS:

Caused by a mutation in the

Fragile X Mental Retardation
One (FMR-1) gene.

Mutation results in expansion

of the CGG triplet within the
FMR1 gene

Mutated gene cannot

properly produce FMR1
protein.

FMRP is necessary for brain

development & functioning
of the nervous system.
 HAEMOPHILIA
Inherited disease where blood
does not clot when exposed to air.
Lack of blood clotting factor VIII
(antihaemophilic globulin, AHG),
& clotting factor IX.
There are two main types of
haemophilia:
 Haemophilia A (deficiency of
functional clotting Factor
VIII).
 Haemophilia B (deficiency of
functional clotting Factor
IX).
Fig: Showing process of formation of blood clot.
 SYMPTOMS :
 Internal bleeding is common in
people with severe haemophilia.
 Most characteristic type of
internal bleed is a joint bleed
where blood enters into the joint
spaces.
 Bleeding in the brain can result in
long-term headaches, seizures or a
decreased level of consciousness.
 Muscle hemorrhage occurs leading
to necrosis.
GENETICS:
 Mutations in the f9 gene leads to the production of abnormal version of coagulation
factor VIII.
 Female carrying the defect on one of her X-chromosomes may not be affected by it.
 If the genes for factor VIII or IX are deficient on a male’s X-chromosome there is no
equivalent on the Y-chromosome & the disorder develops.
 COLOUR-BLINDNESS
We have three colour receptors each of which is made by a
gene.
•Rods – “See in shades of grey”
Cannot distinguish different wavelengths (colors) of
light. More sensitive to low light. Used for night-
vision.
• Cones – “See in colors”
Three types of cones;
differ in which photoreceptor protein (opsin) they make.
1. L-cones sense long-wavelength (red) light.
Make the long-wavelength opsin protein.
2. M-cones sense medium-wavelength (green)light.
Make the medium-wavelength opsin protein.
3. S-cones sense short-wavelength (blue) light.
Make the short-wavelength opsin protein.
 Types of colour-vision deficiency:
 Trichromacy (“three-color vision”)
 Normal Color Vision
 Anomalous Trichromacy (unusual three-color vision)
 See all three primary colors.
Defect in L-cone
 One color is seen weakly
Normal (poor red vision)
 Protanomaly (L-cone defect) red-weak
 Deuteranomaly (M-cone defect) green-weak
 Tritanomaly (S-cone defect) blue-weak

 Dichromacy (“two-color vision”)

 See only two of the three primary colors
 One type of cone is totally absent or Defect in M-cone
nonfunctional. (poor green
 Protanopia (L-cone absent) vision)
 Deuteranopia (M-cone absent)
 Tritanopia (S-cone absent)

 Rod Monochromacy (no cones at all--“no-color

vision”)
 Sees no colors, only shades of gray.
Both protans & deutans are known as “red-green colour- Defect in S-cone
blind”. (poor blue vision)
 Fig. : Difference
between Normal vision
and colourblind vision
PEDIGREE ANALYSIS FOR X-LINKED DOMINANT DISEASES:
PEDIGREE ANALYSIS FOR X-LINKED RECESSIVE DISEASES:
 Skips generations—is passed
from grandfather to grandson
through carrier mother.
 Seen in males. Not expressed in
females unless homozygous
recessive.
 Affected males will have 50%
daughters as carriers.
 Affected mothers will have 50%
carrier daughters & 50% sons
affected
 CONCLUSION
 Genes located on the X chromosome are
called X-linked genes.
X-linked inheritance refers to the pattern
of inheritance of a condition caused by a
faulty gene on the X chromosome.
The faulty gene may be recessive or
dominant.
Conditions that follow a pattern of X-
linked recessive inheritance include
haemophilia and colour-blindness, etc.
The chance that a child will inherit an X-
linked recessive condition in every
pregnancy is different for sons and
daughters and depends on whether the
mother or father has the faulty gene.
 References
Lyon, Mary F. "Sex chromatin and gene action in the mammalian X-chromosome."
American journal of human genetics 14.2 (1962): 135.

 Thomas, George H. "High male: female ratio of germ-line mutations: an alternative

explanation for postulated gestational lethality in males in X-linked dominant disorders."
American journal of human genetics 58.6 (1996): 1364.

 Wettke-Schäfer, Roswitha, and Gisela Kantner. "X-linked dominant inherited diseases

with lethality in hemizygous males." Human genetics 64.1 (1983): 1-23.

 Barker, David F., et al. "Identification of mutations in the COL4A5 collagen gene in Alport
syndrome." Science 248.4960 (1990): 1224.

 Jais, Jean Philippe, et al. "X-linked Alport syndrome natural history in 195 families and
genotype-phenotype correlations in males." Journal of the American Society of Nephrology
11.4 (2000): 649-657.

 Yamazaki, Yuji, et al. "Increased circulatory level of biologically active full-length FGF-23
in patients with hypophosphatemic rickets/osteomalacia." The Journal of Clinical
Endocrinology & Metabolism 87.11 (2002): 4957-4960.

 Glorieux, Francis H., et al. "Bone response to phosphate salts, ergocalciferol, and calcitriol
in hypophosphatemic vitamin D-resistant rickets." New England Journal of Medicine 303.18
(1980): 1023-1031.
 References (cont.)
Holm, Ingrid A., et al. "Mutational analysis and genotype-phenotype correlation of the PHEX
gene in X-linked hypophosphatemic rickets." The Journal of Clinical Endocrinology &
Metabolism 86.8 (2001): 3889-3899.

Garber, Kathryn B., Jeannie Visootsak, and Stephen T. Warren. "Fragile X syndrome."
European Journal of Human Genetics 16.6 (2008): 666-672.

Sutcliffe, James S., et al. "DNA methylation represses FMR-1 transcription in fragile X
syndrome." Human molecular genetics 1.6 (1992): 397-400.

 Pieretti, Maura, et al. "Absence of expression of the FMR-1 gene in fragile X syndrome." Cell
66.4 (1991): 817-822.

 Lee, C. A., et al. "Factor VIII inhibitors in mild and moderate‐severity haemophilia A."
Haemophilia 4.4 (1998): 558-563.

 Morrison, A. E., and C. A. Ludlam. "Acquired haemophilia and its management." British
journal of haematology 89.2 (1995): 231-236.

Wong, Bang. "Points of view: Color blindness." nature methods 8.6 (2011): 441-441.

Ishihara, Shinobu. "series of plates designed as tests for colour-blindness." (1936).

Yokoyama, Shozo, and F. Bernhard Radlwimmer. "The molecular genetics and evolution of red
and green color vision in vertebrates." Genetics 158.4 (2001): 1697-1710.