Overview
Autosomal Dominant
Inheritance
„ Review of some basic concepts of mendelian inheritance
„ Characteristics of autosomal dominant inheritance in man
Mohammad Keramatipour MD, PhD
„ Examples of human autosomal dominant disorders
Keramatipour@tums.ac.ir
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Review of Basics
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Mendel’s Work
„ Mendel’s experiments:
¾ Genes come in p
pairs ((Mendel: factors))
¾ Genes can have different alleles, some (dominant
traits),
), exert their effects over others (recessive
(
traits))
¾ At meiosis alleles segregate from each other (each
gamete receives one allele)
¾ The segregation of different pairs of alleles is
independent
„ Unifactorial inheritance:
¾ First described by Mendel in 1865 “Versuche uber
Pflanzen Hybriden” – Experiment on Plant Hybrids
¾ Republished in 1901 by Bateson: Mendelain inheritance
became synonymous with unifactorial inheritance
¾ Refers
R f
to those
h
trait/
i / di
disorders
d
that
h are d
due to the
h
inheritance of a single gene
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„ Mendel’s own words:
¾ Dominant, recessive
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Dominant vs. Recessive
Definitions
„ Dominant
Dominant:: a phenotype expressed in the same way in both
„ Distinction is not absolute, specially in medical terms??
h
homozygote
t and
dh
heterozygote
t
t
„ Many dominant traits have different phenotype in
heterozygous and homozygous states
„ Recessive
Recessive:: a phenotype expressed only in homozygote
¾ True dominant human disorders
8 Huntington disease
8 Multiple endocrine adenomatosis I
„ Incomplete dominant or semi
semi--dominant
dominant:: phenotype of
heterozygous state, AB, is intermediate between the
phenotypes
p
yp of AA and BB
„ Many recessive traits have heterozygous manifestation at
„ Co
Co--dominant
dominant:: phenotype of AB displays the phenotypic
cellular biochemical
cellular,
biochemical, or molecular level
features of both the homozygotic states
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¾ Sickle cell disease
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Continue to next page
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Dominant vs. Recessive
Monogenic Inheritance
„ Sickle cell disease:
¾
„ Properties:
Clinical level: patients are homozygous for a defective allele
at the Beta globin locus and produce Hb S instead of normal
Hb A: clinically, a recessive disease
¾ Different phenotype result from alternative genotypes
att a single
i l llocus
¾ Number of genotypes & phenotypes are small
¾ Biochemical level: heterozygotes produce Hb S and Hb A,
so at the level of hemoglobin synthesis
synthesis, co
co--dominant
¾ Physiologic level: the normal allele is incompletely dominant
and defective allele is incompletely recessive because a
proportion of red blood cells in heterozygotes show the
sickling phenomenon and they have mild anemia
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¾ Relationship between genotype and phenotype is
simple
i l
¾ Well
Well--suited for analysis using crosses and pedigree
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Mechanisms of Dominance
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Haploinsufficiency
„ Default mechanism:
mechanism: mutations produce recessive alleles to
„ Haploinsufficiency
Haploinsufficiency:: arise when 50
50%
% reduction in amount
or activity of the gene product result in abnormal
phenotypic
h
t i ffeatures
t
„ Commonly occurs with mutation in genes encoding
transcription factor (or other regulatory proteins)
proteins), structural
proteins, and cell surface receptors
the wildwild-type allele because they produce inactive alleles
¾ Most recessive disorders in human are enzyme defects
¾ Most dominant conditions shows aberrant structural or
developmental problems
„ Why
Wh some mutant
t t alleles
ll l show
h
d
dominance:
i
„ Example:
¾ Waardenburg syndrome
¾ Angioneurotic
A i
ti edema:
d
mutation
t ti iin Cl esterase
t
inhibitor
i hibit
gene
8 Due to rapid removal of the protein from circulation
(independent of its concentration) production of large
quantities of protein is needed
¾ Haploinsufficiency
¾ Gain
G i -ofGainoff-function
f
ti mutations
t ti
¾ New (sometimes toxic) protein function
¾ Dominant negative mutation
¾ Recessive mutations with dominant effects
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Waardenburg Syndrome - Type I
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Waardenburg Syndrome
„ AD condition caused by point mutation in PAX3 gene that
codes for a DNA binding protein (2q35)
„ PAX3: expressed in developing neural crest &
dermatomyotomal components of somites
somites,, that give rise
to skeletal muscles and dermis
„ Loss of function mutation in PAX3: deficiency of neural
crest derivatives such as melanocytes in hair
hair, eyes
eyes, inner
ear, causing white forelock, white eyelashes, pachy
depigmentation,
depigmentation
dep
g e tat o , se
sensorineural
so eu a dea
deafness,
ess, a
and
d…
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GainGain
-of
of-Function Mutations
Achondroplasia
„ May happens by:
„ Increased gene dosage:
¾ Hereditary sensory and motor neuropathy type 1: duplication of
PMP22
PMP
22 gene, codes for peripheral myelin protein 22
„ AD condition, mutation in FGFR
FGFR3
3 on
4p16
16..3
¾ 98
98%
% point mutation, GG-to
to--A transition
¾ 1% GG-t0-C transversion at N
N1138
1138
„ Ectopic or temporally altered mRNA expression:
¾ Mutation affects the time or place of gene expression
¾ Usually involves the regulatory part of the gene
¾ Hereditary persistence of fetal hemoglobin: caused by mutation in
globin promoter region and prevent the normal switch between γglobin to δ and β-globin
¾ Both cause substitution of an arginine for
a glycine at position 380 (G
(G380
380A)
A)
¾ 80
80%
% of cases de novo mutation
¾ Paternal age effect
¾ Defect:
8 Zone of chondroblast proliferation in the
physeal
h
l growth
th plates
l t
„ Increased protein activity: due to increased halfhalf-life or activity
¾ Achondroplasia
A h d l i
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New Protein Function
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Dominant Negative Mutation
„ New protein function:
„ If a mutant allele interferes with the wildwild-type allele this is
termed a dominant negative mutation
¾ A missence mutation in the alpha1 antitripsin gene convert
the protein to an inhibitor of thrombin, resulting in a severe
bleeding disorder
„ This could occur in multimeric proteins
„ Various types of collagen proteins
„ Toxic protein alteration
¾ Hereditary amyloidoses:
amyloidoses: mutation in trans
trans--thyretin gene
„ Osteogenesis imperfecta: mutation in the central portion
leads to resistance of protein to proteolysis and increases
th stability
the
t bilit off th
the protein.
t i P
Protein
t i th
then accumulates
l t and
d
undergoes multimerization in the cell as fibrils causing
disruption of the cell
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of the collagen subunit genes
„ Marfan Syndrome
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Recessive Mutation with Dominant Effects
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Autosomal Dominant Inheritance
„ Mutations clinically show dominant pattern of inheritance in
the family
„ More than half of known mendelian traits are dominant
„ At the cellular or molecular level are recessive
„ It happens in most of the dominantly inherited familial
„ Autosomal dominant disorders have high incidence:
¾ ~ 1/500 for familial hypercholesterolemia
¾ ~ 1/500 in hypertrophic
yp
p
cardiomyopathy
y p y
¾ ~ 1/1000 for myotonic dystrophy
¾ ~ 1/ 2500 - 3000 for several other conditions such as
neurofibromatosis
fib
t i and
d Huntington
H ti t disease
di
cancer syndromes (a germline mutation in a tumor
suppressive gene + a “second hit”)
„ RBRB-1 (retinoblastoma gene) is a classic example
¾ Heterozygous cells for the mutation are normal, so mutation
itselff is recessive
¾ Disease results through transmission of a first mutation with
a second somatic mutation in the normal allele of a retinal
cell (two
(two--hit hypothesis)
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Monogenic AD CVDs
Pedigree Pattern
„ In general term:
„ Long QT syndrome: AD, ( also AR)
„ Hypertrophic cardiomyopathy (HCM): AD
¾ Phenotype usually appears in every generation, each
„ Familial hypercholesterolemia: AD
affected person has an affected parent
¾ 50
50%
% risk of inheriting the trait for any child
¾ Normal family members do not transmit the phenotype
to their children
¾ Males and females are equally likely to transmit the
phenotype
¾ Male to male transmission
„ Familial defective apolipoprotein B ((apo
apo B): AD
„ Brugada syndrome: AD (SCN
(SCN5
5A)
„ Marfan syndrome: AD (FBN
(FBN1
1, TGFBR
TGFBR2
2)
„ Restrictive cardiomyopathy
cardiomyopathy:
y p y: AD ((Desmin
Desmin,..)
,..))
„ …..
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Pedigree Example
„ Autosomal Dominance Inheritance
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Counseling: Autosomal Dominant
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Reduced Penetrance, Variable Expressivity
„ Important issues:
¾ New mutation
8 Isolated cases
8 Advanced parental age
8 Low reproductive fitness
„ Mechanism of reduced penetrance and variable
expressivity:
¾ Environmental factors
¾ Somatic mutations
¾ Unstable DNA triplet repeat sequences
¾ Age of onset
¾ Germ
Germ--line mosaicism
¾ Clinical heterogeneity due to
8 Reduced penetrance
8 Variable expression
p
8 Pleiotropy
8 Anticipation
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¾ Genetic background
g
¾ New dominant mutations
¾ Somatic mosaicism
¾ Gonadal (germline) mosaicism
8 Osteogenesis imperfecta: 15
15%
% of cases
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Familial Hypercholesterolemia
LDL Metabolism
„ Low Density Lipoprotein Receptor (LDLR) mutation
„ 5% of patients with hypercholesterolemia
„ High incidence: 1/200 to 1/1000
„ Pathogenesis:
¾ Muatation in LDLR
¾ Plays a key role in cholesterol homeostasis
¾ LDLR is responsible for clearance of cholesterol from
circulation
i l ti
¾ Mutation disrupt the clearing process of cholesterol and
the disease caused due to high level of cholesterol in
circulation
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Phenotype of the Disease
LDLR Pathway & Cholesterol Metabolism
„ Age of onset
¾ Heterozygotes: Early ro middle adulthood
¾ Homozygotes: Childhood
„ High cholesterol level (the earliest finding
finding, usually at
birth)
„ Atherosclerosis, Coronary Artery Diseases (main cause
of death)
„S
Skin (tendon)
(te do ) xanthomas
a t o as
„ Recurrent polyarthritis and tenosynovitis
„ Arcus cornea
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FH, More Sever in Males
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Xanthomas in FH
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Xanthomas in FH
Genetics of FH
„ Mutation in LDLR
„ 2-10
10%
% are large insertions, deletions, or rearrangements
mediated by recombination between Alu repeats within
LDLR gene
„ Some mutations are dominant negative
„ Most mutation are private mutations (allelic
heterogeneity)
„ In some population there are founder effects (high
prevalence of one mutation)
„ Homozygotes have a sever form of the disease
„ Mutation may
y disrupt
p different stages
g of LDLR synthesis,
y
,
transport and ….
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LDLR Mutations
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Diagnosis and Management
Long QT Syndrome
„ Characterized by prolonged ventricular depolarization
„ Diagnosis
¾ Clinical findings
¾ Increased QQ-T interval
¾ Family history
¾ Deformation of T wave & presence of U wave
¾ Laboratory findings
¾ Genetic testing
8 Prenatal diagnosis
g
is p
possible in suitable families
„ Management
¾ Lowering
gp
plasma level of cholesterol is the key
y target
g
¾ Diet: low
low--fat, high
high--carbohydrate diet
¾ Drug
g therapy
py
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Facts About LQT
Types of LQT Syndrome
„ Birth incidence: 1/5000 – 1/7000
„ Genetics of LQT:
¾ Mainly Autosomal dominant
8 Romano
Romano--Ward syndrome
¾ Sometimes recessive
8 Jervell and Lange
Langeg -Nielsen syndrome
y
¾ Genetic heterogeneity
¾ Mutation effects:
8 Loss of function: Potassium channels genes
8 Gain of function: Sodium channels genes
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LQTS Type
Chromosomal
Locus
Mutated Gene
Ion Current
Affected
LQT1
11p15.5
KVLQT1
IKs
LQT2
7q35--36
7q35
HERG
IKr
LQT3
3p21--24
3p21
SCN5A
INa
LQT4
4q25--27
4q25
?
?
LQT5
21q22.1--22.2
21q22.1
KCNE1
(heterozygotes)
IKs
LQT6
21q22.1--22.2
21q22.1
MiRP1
IKr
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Cardiac Arrhythmias
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Management/ Treatment
„ Ventricular tachycardia
„ Genetic:
¾ Torsades de Pointes
¾ Genetic testing available
8 80
80%
% mutation detection rate
8 PND and PGD is possible
p
¾ Ventricular fibrillation
„ Syncope
„ Cardiac arrest
¾ Gene therapy
„ Sudden death
„ Others:
¾ Beta
Beta--blockers
¾ Pacemaker
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Hypertrophic Cardiomyopathy
Dilated Cardiomyopathy
„ Dilated cardiomyopathy
„ Hypertrophic cardiomyopathy (HCM)
¾ Asymmetric
y
left ventricular hypertrophy
yp
p y
¾ Usually autosomal dominant
¾ Prevalence: ~ 1:500
¾ Traditionally an idiopathic disorders
¾ Today is a sarcomere disorder
¾ Mutation
M t ti in
i around
d 11 genes that
th t encode
d different
diff
t element
l
t
of sarcomere
¾ Genetic testing available in many center in US for majority
of genes (MYH7
(MYH7, TPM1
TPM1, MYBPC
MYBPC3
3, ….)
¾ Detection rate: 50
50--60%
60% in patients
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¾ Dilatation and impaired
p
contraction of left ventricle ((or both))
¾ Alcohol abuse, viral myocarditis, metabolic disorders, ..
¾ 30 – 50
50%
% of DCM have g
genetic cause
¾ Mainly autosomal dominant (Troponin T, Beta Mysin Heavy
Chain, …)
¾ X-linked form also (dystrophin)
¾ Genetic testing available at least for 4 genes causing
disease
di
¾ First degree relatives are being screened
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Marfan Syndrome
Thank you for listening, any comments?
„ Autosomal dominant
„ Prevalence 1/3000 – 1/5000
„ Genes:
¾ Type I: FBN1
FBN1
¾ Type II: TGFBR
TGFBR2
2
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