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Lecture 7
X-Linked Inheritance
X-linked recessive disorders
• Responsible gene on X chromosome
• For females, both copies of the X
chromosome must be affected
• Males, hemizygous for the X chromosome,
much more likely to be affected
Some Common
Sex-Linked Recessive Disorders
• Duchenne and Becker Muscular Dystrophy
• Hemophilia A
• Glucose-6-phosphate dehydrogenase deficiency
• Fragile X Mental Retardation
• Color blindness
Paternal
Hemophilia A
Maternal
X
x
X
XX
Xx
1/4
Y
XY
1/4
XY
1/4
1/4
F
M
unaffected 1/2 1/2
non-carrier
unaffected 1/2
carrier
Predict possible fetal
outcomes
affected
1/2
Haemophilia A
An X-linked recessive disease
 Caused
by mutation in the clotting factor VIII
gene (F8) on chromosome Xq28
 Incidence: 1/5,000
males births
Clinical symptoms
Haemorrhage into joints and muscles,
easy bruising, and prolonged bleeding
from wounds.
X-inactivation, Dosage compensation, and the
expression of X-linked genes
Same amount of X-linked gene products
between males and females

Males
 One X chromosome
 Females
 Two X chromosomes
 And yet, the mean amounts of gene products of X-linked
genes are the same in males as in females
 HOW?
 Through X chromosome inactivation
The molecular mechanism behind Xinactivation

The key player is the X-linked gene XIST



X(inactive)-specific transcript
Chromosome Xq13.2
XIST is transcribed to produce a non-coding RNA
that “coats” the X-chromosome and inactivates it
 XIST is uniquely expressed from the inactive X
 XIST RNA does not travel over to any other X
chromosome in the nucleus.
 Barr bodies are inactive X chromosomes
"painted" with XIST RNA.


Transcription of XIST ceases on the other X
chromosome allowing all of its hundreds of
other genes to be expressed. The shut-down of
the XIST locus on the active X chromosome is
done by methylating XIST regulatory
sequences.
So methylation permanently blocks XIST
expression and permits the continued
expression of all the other X-linked genes.
The XIST gene on one of the two X-chromosomes
is randomly inactivated by DNA methylation
The active XIST is transcribed and
its RNA product coats the X-chromosome
XIST
The histones on the coated X undergo methylation
which causes the chromosome to condense,
forming a Barr body, and renders it inactive
X with
inactive XIST
The uncoated X is
left transcriptionally
active
Barr body
X with
active XIST
X inactivation by X inactivation-specific transcript (Xist)
Barr bodies
Expression of X-linked Genes in
Heterozyotes

Inactivation is random, established when
embryo < 100 cells  fraction of cells in carrier
female with normal or mutant allele tend to be
variable
 Thus, clinical variation in expression of X-linked
disorders is common in heterozygotes ranging
from normal to affected
 A manifesting heterozygote is a female in whom
the deleterious allele is on the active X in most
or all of cells (an extreme e.g., of unbalanced or
skewed X-inactivation)
X chromosome Inactivation

Inactivation is not always random



Inactivation is not complete


A structurally abnormal X is preferentially inactivated, e.g.,
isochromosome X
E.g., extraembryonic membranes (that go on to form the amnion,
placenta, and umbilical cord). In all the cells of the
extraembryonic membranes, it is father's X chromosome that is
inactivated.
Some genes are known to escape inactivation (i.e. those with a
functional homolog on the Y, e.g., genes located in the
pseudoautosomal region)
Inactivation is not permanent

reversed in development of germ cells (not passed on to
gametes)
X-autosome translocation
There is normally a 50% chance that
a particular X will be inactivated in a cell
from a female
If an X bears a piece of autosome
(translocation) then the untranslocated X is
always inactivated since the cell needs both
copies of the autosomal genes to be active
If the translocated X has a mutant allele, all the
woman’s cells will be mutant
Functional Mosaicism Resulting from Xinactivation
 Females
are mosaics wrt their X-linked
genes
 Mosaicism is readily detected for some
disorders e.g., DMD
Immunostaining for dystrophin in
muscle specimens. A, A normal
female (magnification ×480).
B, A male with Duchenne muscular
dystrophy (×480).
C, A carrier female (×240).
Staining creates the bright lines seen
here encircling individual muscle
fibers. Muscle from DMD patients
lacks dystrophin staining. Muscle
from DMD carriers exhibits both
positive and negative patches of
dystrophin immunostaining, reflecting
X inactivation
Example: hemophilia A
P
Predict possible fetal outcomes
paternal
maternal
X
x
X
Y
XX
XY
Xx
1
2
xY
1
2
female
male
1
4
1
4
1
4
1
4
female carriers
female non-carriers
male affected
male unaffected
1
2
1
2
x
1
2
X
1
4
xX female carrier
Y
1
4
xY male affected
X
1
4
XX female non-carrier
Y
1
4
XY male unaffected
maternal
1
2
X
1
2
1
2
paternal
Homozygous Affected Females
Consanguinity in an X-linked recessive pedigree for red-green
color blindness, resulting in a homozygous affected female
New Mutation in X-linked Disorders
• For a sex-linked recessive disorder with zero
fitness, such as Duchenne muscular dystrophy,
1/3 of disease alleles are in males and are lost
with each generation. Thus, 1/3 of disease
alleles must be replaced with a new mutation in
each generation
• DMD is said to be genetic lethal because
affected males usually fail to reproduce
• For hemophilia, in which reproduction is reduced
but not eliminated, a proportionately smaller
fraction of cases will be due to new mutation
Characteristics of Sex-Linked
Recessive Inheritance
 Males are more commonly affected than females.
 The gene responsible is transmitted from an affected man
through his daughters, who are seldom affected. Each daughter is
an obligatory heterozygous carrier. Each of the carrier daughter's
sons has a 50% chance of inheriting it.
 No male to male transmission occurs.
 The affected males in a pedigree are usually related through
females.
 Heterozygous female carriers are usually unaffected, but some
may express the condition with variable severity (“Lyonization”).
X-Linked Dominant Inheritance
• Responsible gene on X chromosome
• The phenotype is regularly expressed in
heterozygotes
• Affected fathers transmit the disorder to ALL of their
daughters none of their sons
• The pattern of inheritance through females is no
different from AD pattern
• Each child of an affected female has a 50% chance
of inheriting the trait, regardless of sex
• Rare X-linked dominant phenotypes are about twice
as common in females, though the expression is
much milder in females who are almost always
heterozygous
X-Linked Dominant Inheritance
• X-linked hypophosphatemic rickets, also called vitamin D-resistant rickets, in
which ability of kidney tubules to reabsorb filtered phosphate is impaired
• Serum phosphate level is less depressed and rickets less severe in heterozygous
females as compared to affected males
• The defective gene product appears to be a member of a family of endopeptidases,
but the pathogenic mechanism is not known
X-linked Dominant Disorders with Male
Lethality

Some rare genetic defects expressed
exclusively or almost exclusively in females
appear to be XD lethal in males before birth
 Typical pedigrees: transmission by affected
female  affected daughters, normal daughters,
normal sons in equal proportions (1:1:1)
 Rett syndrome meets criteria for an XD that is
usually lethal in hemizygous males. The
syndrome is characterized by normal prenatal
and neonatal growth and development, followed
by rapid onset of neurological symptoms and
loss of milestones between 6 and 18 months of
age.
Rett syndrome cont.

Children become spastic and ataxic, develop autistic
features and irritable behavior with outbursts of
crying, and demonstrate characteristic purposeless
wringing or flapping movements of hands and arms.
 Head growth slows and microcephaly develops.
Seizures are common (~50%)
 Mental deterioration stops after a few years and the
patients can then survive for many decades with a
stable but severe neurological disability.
 Most cases caused by spontaneous mutations in an
X-linked MECP2 gene encoding methyl CpG binding
protein 2. ? Thought to reflect abnormalities in
regulation of genes in developing brain.
Typical appearance and hand posture of girls
with Rett syndrome
Rett syndrome cont.

Males who survive with the syndrome usually have
two X chromosomes (as in 47,XXY or in a
46,X,der(X) male with the male determining SRY
gene translocated to an X) or are mosaic for a
mutation that is absent in most of their cells
 There are a few apparently unaffected women
who have given birth to more than one child with
Rett syndrome. ? X-inactivation pattern in a
heterozygous female. ? Germline mosaic
Pedigree pattern demonstrating an X-linked dominant disorder, lethal in
males during the prenatal period.
Characteristics of X-Linked Dominant
Inheritance
• Affected fathers with normal mates have no
affected sons and no normal daughters
• For rare pehnotypes, affected females are about
twice as common as affected males (unless
disease is lethal in males), but affected females
typically have milder (though variable) expression
• Both male and female offspring of a
heterozygous female have a 50% risk of
inheriting the phenotype. The pedigree pattern is
similar to AD inheritance
Patterns of Pseudoautosomal Inheritance

Genes on pseudoautosomal region can regularly
exchange b/w the two sex chr’s
 E.g., Dyschondrosteosis, a dominantly inherited
skeletal dysplasia with disproportionate short
stature and deformity of the forearm


The responsible gene is pseudoautosomal that escapes
X-inactivation, encodes a transcription factor likely
involved in stature
Either deletion/mutations  dyschondrosteosis in both
heterozygous males and females
Inheritance pattern of dyschondrosteosis. Arrow shows a male
who inherited the trait on his Y chr. from his father. His father,
however, had inherited the trait on his X chr. from his mother