Transcript Single gene disorders

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More than half of Mendelian phenotypes are
autosomal dominant
Examples:
Familial hypercholesterolemia
 Myotonic dystrophy
 Huntington disease
 Neurofibromatosis
 Polycystic kidney disease**
 Achondroplasia
-------------------------------------------------------** Less common AR form exisits
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In typical AD inheritance, every affected
person in a pedigree has an affected parent
This is also true for X-linked dominant traits
Male-to-male transmission can readily
distinguish AD phenotypes
?
Familial
hypercholesterolemia
Punnett Square
“a” = normal allele
“A” = mutant allele
Maternal
P
A 1/2
What is the
probability that this
pregnancy will be
affected?
a Aa
Paternal
1/2
a Aa
1/2
a 1/2
aa
1/4
1/4
+
aa +
1/4
1/4
affected unaffected
1/2
1/2
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New alleles arise by mutation and are
maintained or removed by selection
Survival of new mutation in the population
depends on the fitness of persons carrying it as
compared to persons with other alleles at the
locus concerned
Many autosomal dominant disorders are
associated with reduced fitness
• Fitness-probability of transmitting one’s genes to
the next generation
• 0 if having the disorder eliminates the ability to
reproduce--ex. Death by age of reproduction
• 1 if the same ability to reproduce as gen. pop.
If the fitness is 0, all affected individuals must be due
to new mutations
If the fitness is 1, i.e., the onset of the disorder is
after reproduction and therefore does not affect it, a
patient is more likely to have inherited the disorder
FITNESS - the relative reproductive
success of a particular phenotype,
between 0 and 100%. It may be
reduced by decreased survival to the
age of reproduction or diminished
fertility.
Hutchinson-Gilford Progeria
• Autosomal Dominant, Zero Fitness
• Always the Result of a New Mutation
• Reported to occur in 1 in 4 million newborns worldwide
Autosomal Dominant disorders frequently have
differences in expression of mutant genes
1. Penetrance: probability of any phenotype
all or none concept
2. Expressivity: severity of the phenotype
in individuals with the same
genotype
3. Pleiotropy: a genetic defect results in diverse
phenotypic effects
Example: Neurofibromatosis
Neurofibromatosis (NF1)-common disorder of the nervous system
1. Multiple benign fleshy tumors (neurofibromas) in the skin
Neurofibromatosis type 1 occurs in 1 in 3,000 to 4,000 people
worldwide
Neurofibromatosis (NF1)-common disorder of the nervous system
2. Multiple flat, irregular pigmented skin lesions known as
café au lait spots
Neurofibromatosis (NF1)-common disorder of the nervous system
3. Small benign tumors (hamartomas) on the iris of the eye
Neurofibromatosis (NF1)-common disorder of the nervous system
4. Less frequently, mental retardation, CNS tumors,
diffuse plexiform neurofibormas and the development
of cancer of the NS or muscle
Adult heterozygotes almost always demonstrate some sign
of the disease  Penetrance is 100% but age-dependent
Phenotype ranges from café au lait spots to tumors of the
spinal cord  Variable expressivity
Pleiotropic  affects skin, iris, brain, muscle
Pedigree of a family with NF-1, apparently originating as
a new mutation in the proband
Example: Split-hand deformity (lobsterclaw malformation) a type of
ectrodactyly
This female is
non-penetrant
Example: BRCA2 Familial Breast Cancer
Although men can get
breast cancer,
penetrance is much
lower than in woman
who inherit BRCA2
mutations
Example: Huntington Disease
% affected
100
25
0
30
80
age in years
?
What is the probability that she has inherited a
huntingtin mutation
given that she's unaffected at 30?
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Genotypes do not act in isolation
Interaction with the wild-type allele
 Interaction with other loci
 Interaction with the environment
 Not known!
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Matings that could produce homozygous
offspring are rare (A/a x A/a, A/A x A/a or
A/A x A/A)
Disorders are usually more severe in
homozygotes
Example 1:
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Achondroplasia: a skeletal disorder of short-limb
dwarfism and large head size
Marriage b/w achondroplastic (heterozygotes) is
common
Homozygous achondroplastic patients are much
more severely affected & commonly do not survive
early infancy
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Short limbs, a normal-sized head and body,
normal intelligence
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Fibroblast growth factor receptor 3
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Inhibits bone growth by inhibiting chondrocyte
proliferation and differentiation
Mutation causes the receptor to signal even in
absence of ligand
Normal FGFR3 signaling
FGF ligand
extracellular
intracellular
FGFR3
Normal FGFR3 signaling
extracellular
intracellular
Inhibition of bone growth
Achondroplasia
Gly380Arg mutation in
transmembrane domain
extracellular
intracellular
*
• Receptor signals in absence of ligand
• Bone growth attenuated
Example 2:
 familial hypercholesterolemia, an AD disorder
leading to premature coronary heart disease
 Homozygotes have a very severe disease with
much shorter life expectancy as compared to
heterozygotes
Cutaneous xanthomas
in a familial
hypercholesterolemia
homozygote.
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HD is a neurodegenerative disease
characterized by progressive dementia and
abnormal movements
HD is an exception in that severity of the
disorder (clinical expression) is the same in
heterozygotes and homozygotes (onset age?)
HD homozygotes can be distinguished from
heterozygotes by molecular analysis of mutant
gene
Defect is autosomally transmitted but
expressed in only one sex
Example:
 male-limited precocious puberty (familial
testotoxicosis), an AD disorder, affected boys
develop 2º sexual characteristics and
adolescent growth spurt at ~ 4 yrs
 In some families, mutation is in leutinizing
hormone receptor gene (mutant receptor
signals without hormone).
 The defect is non-penetrant in heterozygous
females (another example of sex-dependent
penetrance)
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Pedigree pattern of male-limited precocious puberty. This AD
disorder can be transmitted by affected males or by unaffected
carrier females. Male-to-male transmission shows that inheritance is
not X-linked. Because the trait is transmitted through unaffected
carrier females, it can not be Y-linked.
• phenotype appears in every generation
• each affected person has an affected parent (exceptions!)
• each child of an affected parent has 50% risk to inherit
trait.
• unaffected family members do not transmit phenotype to
children (exceptions again).
• males and females equally likely to transmit the trait, to
children of either sex. In particular, male-to-male
transmission does occur (in contrast to sex-linked
dominant inheritance).
• new mutations relatively common