Genetics
Mutations
 Point mutation
– Missense mutation
– Nonsense mutation
 Frameshift mutation
 Trinucleotide repeat mutation
Mutations:
 Decreased gene product or inactive protein:
 Enzymes:AR
 Regulation of complex metabolic pathways: e.g., LDL receptor
 Key structural proteins: dominant negative
 Gain of function:
 Almost always AD, e.g., Huntington disease
Mendelian Disorders
 Expressed mutations
in single genes of
large effect
 Gene expression
– Dominant
– Recessive
– Codominant
 Pleiotropism vs
genetic heterogeneity
Autosomal Dominant Disorders
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Onset: older age
Reduced penetrance
Variable expressivity
New mutation:
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Frequency depends on reproductive capability
In egg or sperm
Germ cells of older fathers
No increased risk in siblings
Examples of AD inheritance
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Huntington disease
Neurofibromatosis
Tuberous sclerosis
Polycystic kidney disease
Familial polyposis coli
Hereditary spherocytosis
Marfan syndrome
Familial hypercholestrolemia
Autosomal Recessive Disorders
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The largest group in Mendelian disorders
Almost all of the inborn errors of metabolism
Enzymes
Complete penetrance
More uniform expression
Early onset
New mutations: ?
Examples of AR inheritance
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Cystic fibrosis
PKU
Lysosomal storage disease
Sickle cell anemia
Congenital adrenal hyperplasia
Ehler-Danlos syndrome
Spinal muscular atrophy
X- Linked Disorders
 No Y- linked inheritance
 Almost all recessive
 Males are hemizygote for X-linked mutant
genes
 Random inactivation of one of the Xchromosomes; partial symptoms,e.g.,
G6PD
Examples of XLR inheritance
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Duchenne muscular dystrophy
Hemophilia A and B
G6PD deficiency
Wiskott-Aldrich syndrome
Diabetes insipidus
Fragile X syndrome
X- Linked Disorders
 Rare X-linked Dominant
– How is the inheritance?
– Such as Vitamin D resistant rickets
Mendelian Disorders
Biochemical & Molecular Basis
 Enzyme defects
 Defects receptors & transport systems
 Alterations in structure, function or quantity
of nonenzyme proteins
 Genetically determined adverse reaction to
drugs
Enzyme Defects
 Enzyme:
– Quantity.
– Quality.
 Decreased product.
– Albinism.
 Increased substrate or
intermediates.
– PKU.
 Ipmaired inactivation of
toxic substrate.
– Alpha1 Antitrypsin D.
Genetically Determined Adverse
Reaction to Drugs
 Pharmacogenetics
– Enzyme deficiency unmasked by drug
administration
 G6PD and Primaquine
Disorders Associated With
Defects in Structural Protein
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Fibrillin: Marfan syndrome
Collagen: Ehler Danlos syndrome
Dystrophin: Duchene/Becker
Spectrin/Ankyrin/Protein 4,1: Spherocytosis
Marfan Syndrome
 Definition:
– Connective tissue (elastic fiber) disorder
– Major involved organs
 Skeleton
 Eye
 Cardiovascular system
 Prevalence: 1/10,000 – 1/20,000
Marfan Syndrome
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Autosomal dominant inheritance
70-80% familial vs 20-30% new mutations
Variable expression: genetically heterogeneous
Mutation
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Almost all
Negative dominant
Chromosome 15q21.1
FNB1 gene
Elastic fibers
 Central core
– Predominantly ellastin
 Peripheral
microfibrillary network
– Predominantly fibrillin
Fibrillin
 Particularly abundant in
– Aorta
– Ligaments
– Ciliary zonules of lens
Marfan Syndrome
 Pathogenesis
– Inherited defect in fibrillin, an extracellular
glycoprotein
– FBN1 gene mutation
 70 different mutation
 Mostly nonsense mutations
Marfan Syndrome
 Skeletal abnormalities
– Most striking
– Usually tall
– Upper segment/lower segment: low
– Long extremities
– Pectus excavatum
– Long tapering fingers and toes
Marfan Syndrome
…Skeletal Abnormalities
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Hyperflexibility of joints
Scoliosis
Kyphosis
Rotation or slipping of thoracic vertebrae
Dolichocephalic (long-headed)
– Cranial index less than 75%
– Cranial endex: width of skull/length of skull
 Bossing of frontal & supraorbital ridges
Marfan Syndrome
Ocular Changes
 Characteristic
– Very rare in those without this disease
 Bilateral subluxation or dislocation of lens
– Ectopia lentis
Marfan Syndrome
Cardiovascular Changes
 Aortic neurysm
– Cystic medionecrosis
 Intimal tear
– Dissection
 Towards root of aorta or iliac
 Ruptured dissection: cause of 30-45% of deaths
– Aortic regurgitation
Marfan Syndrome
...Cardiovascular Changes
 Mitral prolapse
– Loss of connective tissue support
– More common
– Less serious
– Floppy valve
– Elongated chordae tendineae
– Similar changes in tricuspid and rarely aorta
Marfan Syndrome
 Diagnosis
– Presymptomatic Dx:
 RFLP
 70 different mutations
– Direct gene diagnosis impossible
Marfan Syndrome
Marfan Syndrome
Marfan Syndrome
Defects in Collagen Synthesis or
Structure
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Osteogenesis imperfecta
Alport syndrome
Epidermolysis bullosa
Ehler Danlos syndrome (EDS)
Collagen
 Most abundant protein in animal world
 At least 14 distinct collagen types
 General formula
– (gly-x-y)n
– Triple helix
 Three a chains: about 30 a chains
Collagen Synthesis
Ehler Danlos Syndrome (EDS)
 Genetically heterogeneous
 At least 10 variant
 Clinical manifestations
– Skin
 Hyperextensible
 Extremely fragile
– Joints
 Prone to dislocation
 Hypermobile
Ehler Danlos Syndrome (EDS)
 Type VI
– Most commom AR form of EDS
– Mutation in lysyl hydroxylase gene
 Only collagen I and III
– Ocular fragility with rupture of cornea and retinal
detachment
Ehler Danlos Syndrome (EDS)
 Type IV
– AD inheritance
– Collagen type III
– At least 3 different mutation:
 Abnormal collagen
 Decreased synthesis
 Decreased excretion
– Some negative dominant
– Rupture of colon and large arteries
Ehler Danlos Syndrome (EDS)
 Type VII
– AD inheritance
– Abnormal procollagen type I
– Peptidase can not cleave the N terminal
– Genes
 a1[I]
 a2[I]
Ehler Danlos Syndrome (EDS)
 Type IX
– XLR inheritance
– Mutation in copper binding protein
 Decreased activity of lysyl hydroxylase
– Cross-linking of collagen & elastic
– High level of copper within the cell
– Low serum copper & ceruloplasmin levels
Ehler Danlos Syndrome (EDS)
Ehler Danlos Syndrome (EDS)
Familial Hypercholestrolemia
 A receptor disease
 The most frequent mendelial disorder
– 3-6% of survivors of MI
 Mutation in the gene encoding LDL receptor
– Hypercholestrolemia
 Premature atherosclerosis: MI
 Xanthoma
Familial Hypercholestrolemia
Heterozygotes
– 1/500
– 2-3 times higher plasma cholestrol
 Homozygotes
– 5-6 times higher plasma cholestrol
– MI before 20 years of age
Familial Hypercholestrolemia
 Pathogenesis
– Decreased LDL clearance (uptake)
– Increased LDL production
 More IDL coverts to LDL
 In both heterozygotes and homozygotes
– Increased LDL uptake by
macrophage/monocyte (scavenger receptor)
 Acetylated or oxidized LDL
Familial Hypercholestrolemia
 LDL receptor gene
– Extremely large
 18 exons
 5 domains
 45 kb
Familial Hypercholestrolemia
 LDL receptor gene
– More than 150 different mutations
 Insertion
 Deletion
 Missense
 Nonsense
– Mutations categorized in 5 groups
Management
 Statins
– HMG-CoA reductase inhibition
 Decreased synthesis of cholestrol
 Increased synthesis of LDL receptor
 Gene therapy
Lysosomal Storage Diseases
 Definition
– Lack of any protein essential for the normal
function of lysosomes
Lysosomal Storage Diseases
 Involved organs depend on
– The site where most of the material to be
degraded is found.
 GM1 & GM2 gangliosidoses
– Brain
 Mucopolysaccharidoses
– All of the body
– The location where most of the degradation
normally occurs
 Mononuclear phagocytes
Lysosomal Storage Diseases
Tay-Sachs Disease
 Most common form of GM2 gangliosidoses
 Ashkenazi jews
– 1/30 carrier rate
 All tissues lack hexosaminidase A
– Including leukocytes and plasma
 GM2 accumulation in many organs
– Heart, liver, spleen,CNS, autonomous nervous
system, retina, ..
Niemann-Pick Disease
 Rare lysosomal storage disease
 Lysosomal accumulation of sphingomyelin
– Sphingomyelinase deficiency
 Common in Ashkenazi jews
 Types A & B
 Previously type C
– Defect in intracellular cholestrol esterification & transport
Sphingomyelin
Present in cell membranes
Niemann-Pick Disease
 Type A
– Severe infantile type
 Extensive neurologic involvement
 Severe visceral accumulation of sphingomyelin
– 75-80% of cases
– Survival: less than 3 years
Niemann-Pick Disease
 …Type A
 Missense mutation
 Complete deficiency of sphingomyelinase
Niemann-Pick Disease
 Type B
– Organomegaly
– No CNS involvement
– Survive adulthood
Niemann-Pick Disease
Diagnosis
 Biochemical studies
– Sphingomyelinase activity in leukocytes and
cultured fibroblasts
 DNA probes:
– Both patients and carriers
Niemann-Pick Disease
Gaucher Disease
 Glucocerebrosidase gene mutation
 Accumulation of glucocerebroside in
phagocytes and sometimes CNS
Gaucher Disease
 Most common lysosomal storage disease
 Types
– I (chronic non-neuropathic): 99%
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Decreased enzyme activity
Without CNS involvement
Predominantly spleen & skeleton
Pancytopenia or thrombocytopenia
Pathologic Fx and bone pain
Progressive but compatible with long life
European Jews
Gaucher Disease
 …types
– II (acute neuropathic)
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No enzyme activity
No predilection for jews
Infantile
Progressive involvement of CNS & early death
Hepatosplenomegaly
Gaucher Disease
 Diagnosis
– Homozygotes
 Enzyme activity
– Peripheral blood leukocytes
– Cultured skin fibroblasts
– Heterozygotes
 Enzymatic methods not reliable
 Detection of mutation
– More than 30 different mutations
Gaucher Disease
 Management
– Difficult
– Replacement therapy
 Recombinant enzyme: extremely expensive
 Bone marrow transplantation
 Gene therapy: future
Glycogen Storage Diseases
 AKA: Glycogenoses
 Genetic disease with metabolic defect in
synthesis or catabolism of glycogen
Glycogen Storage Diseases
 Hepatic type
– Hepatomegaly
– Hypoglycemia
– Examples
 Von Gierke: Glucose-6-phosphatase (I)
 Liver phosphorylase (VI)
 Debranching enzyme(III)
Glycogen Storage Diseases
 Myopathic type
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Muscle weakness
Cramps following exercise
Following exercise lactate does not increase
Examples
 McArdle: muscle phosphorylase(V)
 Muscle phosphofructokinase (VII)
Glycogen Storage Diseases
 Miscellaneous
– Pompe (acid maltase, a-glucosidase)
 Lysosomal accumulation of glycogen
 Predominantly heart involvement
 Early death
Pompe Disease
Disorders With multifactorial
Inheritance
 Some normal phenotypes
– Height
– Intelligence
– Eye & hair color
Normal Distribution
x_
-2.58x
-1.65x
-1.96x
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+1.65x
+2.58x
+1.96x
90% Samples
95% Samples
99% Samples
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Disorders With multifactorial
Inheritance
 Different diseases
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Cleft lip & palate
Congenital heart disease
Coronary heart disease
HTN
Gout
DM
Pyloric stenosis
Disorders With multifactorial
Inheritance
 Both environment and two or more mutant
genes (dosage effect)
 Not polygenic inheritance
 Variable expressibility
 Reduced penetrance
 First rule out mendelian & chromosomal
inheritance
Disorders With multifactorial
Inheritance
 Risk of expression: # of mutant genes inherited
– Severity of disease
– # of diseased individuals
 The rate of recurrence of the disorder (in range of
2-7%) is the same for all first-degree relatives of
affected individuals
 Identical twins: concordance 20-40%
 Expression of multifactorial trait
– Continuous: height
– Discontinuous: DM