X-Linked Inheritance by Mg7kd8


									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
              Hemophilia A                Maternal
                                        X       x
                                    X   XX         Xx

                                             1/4        1/4

                                    Y   XY         XY
                                             1/4        1/4

                                                   F      M
                                        unaffected 1/2 1/2

                                        unaffected 1/2

                                        affected         1/2
Predict possible fetal
              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 X-

   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

   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

The histones on the coated X undergo methylation
  which causes the chromosome to condense,
   forming a Barr body, and renders it inactive

                                                               X with         X with
                                                            inactive XIST   active XIST

                                The uncoated X is
                               left transcriptionally

                   Barr body
X inactivation by X inactivation-specific transcript (Xist)
Barr bodies
      Expression of X-linked Genes in
 Inactivation is random, established when
  embryo < 100 cells  fraction of cells in carrier
  female with normal or mutant allele tend to be
 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
       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

   Inactivation is not complete
       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
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 X-
 Females   are mosaics wrt their X-linked
 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
               X      x                1

                                       4   female carriers
           X   XX    Xx   2   female   1
                                           female non-carriers
                          1            1
           Y   XY    xY   2   male     4   male affected
                                           male unaffected
               1         1
               2   X     4   xX female carrier
       2   x   1         1
               2   Y     4   xY male affected
               1         1
       1       2   X     4   XX female non-carrier
       2   X
               1         1
               2   Y     4   XY male unaffected
        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

 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
• 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
            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
 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
    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

• 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

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