Xlinked inheritance Sexlinked inheritance

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X-linked inheritance (Sex-linked inheritance)

• caused by mutant genes on X chromosome
• -few, if any genes on Y chromosome but
  contains testis determining factor (TDF)
• males are hemizygous (XY)
• ? mutant genes expressed

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X-linked inheritance (Sex-linked inheritance)
(cont.)

• - females have two X chromosomes (XX), but only
  one is active (X-inactivation)
• ? variable expression of X-linked genes
• X-linked recessive rarely expressed in women
• X-linked dominant usually expressed in women

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Characteristics of X-linked recessive inheritance

• Trait is more frequent in males than females
• Mutant gene expressed in hemizygous males, or in
  homozygous females
• All daughters of affected males are carriers, and
  their sons have 50 risk of being affected
• (?skipped generations)
• No male to male transmission
• Occasional variable expression in heterozygous
  women because of X-inactivation (Lyonization)

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Duchenne Muscular Dystrophy (DMD)

• X-L recessive
• -progressive weakness and loss of muscle
• -symptoms by 5 yrs, in wheelchair by 11 yrs,
  death in late teens or early 20s
• 5-10 of carrier females have muscle weakness, a
  few have severe disease
• very large gene (gt2.5 Mb)
• -protein is called dystrophin
• -most mutations are deletions
• -Becker Muscular Dystrophy is allelic

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X-Inactivation Lyon Hypothesis
(Lyonization)

• FEMALES , XX - BUT ONLY 1 X ACTIVE
• - INACTIVATION IS RANDOM
• - OCCURS EARLY IN EMBRYONIC LIFE
• - CLONAL
• - RESULTS IN VARIABLE EXPRESSION OF
  HETEROZYGOTES (X X)
• - MOSAICISM (e.g. COAT COLOUR GENES)

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EXCEPTIONS

• 1. Affected son of affected man
• -because mother is a carrier
• - either common condition
• e.g. colour blindness
• or
• - consanguinity
• e.g. Hemophilia in Twillingate
• (could also have affected females --
  XX )

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EXCEPTIONS (cont.)

• 2. Severely affected female of lethal X-linked
  condition e.g. DMD
• either - non-random inactivation of normal
  gene in heterozygote (XX)
• - X0 female (Turner syndrome)
• - X-autosome translocation through gene
  

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Characteristics of X-linked dominant inheritance

• 1. Both males and females may be affected, but
  approximately twice as common in women
• 2. No male to male transmission (same as X-LR)
• 3. All daughters of affected man will be affected
  (different from AD)
• 4. Both sons and daughters of affected women have
  50 risk of being affected (same as AD)
• 5. Affected women often have milder and more
  variable phenotype than affected men

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Genetic lethal in males

• Affected males fail to reproduce
• e.g. DMD (Duchenne Muscular Dystrophy) (XLR)
• - 1/3 of patients represent new
  mutations
• - 2/3 have carrier mothers
• Prenatal lethal in males (XLD)
• ? only females affected
• If affected females do not reproduce
• -all new mutations (looks like a sporadic
  condition)
• eg RETT syndrome
• If affected women do reproduce
• - fewer males than expected (all
  unaffected)

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