BHS 116 - Physiology
Notetaker: Jessica Kulick
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Date: 10/12/2012, 2nd hour
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Genetic Disease
o Hereditary (familial) disorders are derived from one’s parents, are transmitted in the
gametes through generations
o Congenital simply implies present at birth (not necessarily hereditary)
 Some congenital diseases are not genetic (congenital syphilis – infant gets
syphilis infection in birthing process)
 Not all genetic diseases are present at birth (Huntington disease – hereditary, not
symptomatic at birth… 3rd or 4th decade)
Caused by mutations
o Mutations are permanent changes in DNA
 Point mutations: missense (1 amino acid swapped for another, still have a protein
made, just varied, like glutamic acid instead of valine) and nonsense (stop codon,
UAG, is the result of the mutation, full protein not made)
 Result from a substitution of a single nucleotide base by a different base
 Sickle cell anemia
 Frameshift mutations: all codons after the mutation are varied and add the wrong
amino acids, can occur when insertion or deletion of 1 or 2 base pairs alters the
reading frame of the DNA strand
 Alters everything downstream
 Cystic fibrosis (3 AAs deleted)
 Trinucleotide repeat mutations: Huntington disease
 Characterized by an amplication of a sequence of 3 nucleotides (multiple
times in the genes)
 The specific sequence differs in various disorders but ALL of the
affected sequences contain the nucleotides guanine (G) and cytosine (C)
as part of trinucleotide
 Fragile X syndrome: 250-4000 repeats of CGG in a single gene instead
of 29 in normal
Mendelian Disorders
o Single gene defects (mutations) follow Mendelian pattern of inheritance
o Autosomal dominant, autosomal recessive, or x-linked
o 5000 characterized
o Pleiotropy: single gene mutation may lead to many phenotypic effects
 Marfan syndrome: affects numerous systems in the body
 Defect in fibrillin protein effects skeleton, eye, and cardiovascular
systems
o Genetic Heterogeneity: mutations at several genetic loci may produce the same trait
 Several spots in 1 gene all lead to once effect
 Retinitis pigmentosa, caused by several types of mutations
o Autosomal Dominant disorders
 Familial hypercholesterolemia
 Huntington disease
 Marfan syndrome
 Manifested in heterozygous state, 1 parent is affected (rare to be homozygous)
 Only need 1 mutant copy to have the disease
 Men and women affected equally
 Men and women can transmit to offspring equally
 Child has a 1 in 2 chance if one parent is affected
 In many cases the symptoms aren’t seen until adulthood
 Mother has one mutant copy, father unaffected
BHS 116 - Physiology
Notetaker: Jessica Kulick
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Date: 10/12/2012, 2nd hour
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 2 of 4 children become affected, 50% chance of symptoms
If mutant in father as well -> 75% chance of offspring having disease, 25%
would be homozygous
In autosomal dominant disorders 50% reduction in the normal gene product is
associated
 Only missing half of the protein the gene encodes
Mostly associated with key structural proteins or proteins involved in the
regulation of complex metabolic pathways
Enzymes are rarely affected
 Even if only a little bit of enzyme -> should have enough that symptoms
wouldn’t be seen
Marfan Syndrome
 Autosomal dominant disorder of connective tissues
 Affected protein is fibrillin-1, component f microfibrils
 Fibrillin-1 encoded by FBN1 gene and mutations to this gene are found
in all patients with Marfan syndrome
 Molecular diagnosis of Marfan syndrome is not possible because there
are over 600 distinct mutations affecting FBN1
 Mutant fibrillin-1 acts as a dominant negative by preventing formation of
normal microfibrils
o When expressed -> negative action -> prevents microfibril
formation in loose connective tissue
 Prevalence is 2-3 per 10,000 with 75% being familial
 Abraham Lincoln
 Affects skeleton, eyes, and cardiovascular systems
 1 gene effected -> effects 3 systems
 Skeleton
o Most obvious
o Elongated features
o Hyperextensibility of joints
o Chest deformed (pigeon-breast, caved in sternum)
o Don’t know why it occurs and affects bones because it’s a CT
disease but there’s thought that there’s another gene effect that
increases stimulation of bone growth
 Cardiovascular system
o Most serious consequences
o Fragmentation of elastic fibers in the tunica media of the aorta ->
can lead to aneurysmal dilation and aortic dissection
 Fibrillin makes walls of larger blood vessels weaker, less
connective tissue proteins, weaker walls -> lots of
aneurysms, aortic dissection if break through one layer
o Valves can be distensible and regurgitant
 Eyes
o Bilateral dislocation or subluxation of the lens due to weakened
suspensory ligament (won’t hold lens in place as well as it
should)
Familial Hypercholesterolemia
 Autosomal dominant disorder involving a metabolic pathway
 Among most common Mendelian disorders: 1 in 500 for heterozygotes
Date: 10/12/2012, 2nd hour
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BHS 116 - Physiology
Notetaker: Jessica Kulick
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Caused by a mutation in the gene encoding the LDL receptor protein
which is involved in transport and metabolism of cholesterol
 3-6% of myocardial infarction survivors have the disorder
o Primary reason for MI’s
 As a consequence of receptor abnormalities, there is a loss of feedback
control
o Elevated levels of plasma cholesterol leads to premature
atherosclerosis which leads to a greatly increased risk of
myocardial infarction
 Heterozygotes (1 mutant gene): have a 2-3X increase in plasma
cholesterol (5-600 range)
o Tendinous xanthomas and premature atherosclerosis
 Xanthomas are cholesterol deposits
 Homozygotes (2 mutant genes): have a 5-6x increase in plasma
cholesterol (thousands range)
o Skin xanthomas and coronary, cerebrall and peripheral
atherosclerosis at an early age (early teens)
o MI may develop before 20 (teens -> most die of fatal heart attack
before mid 20’s -> can’t metabolize any cholesterol)
 Under normal circumstances the liver synthesizes and secretes VLDL
which is carried to other tissues (adipocytes, muscle) where it is
converted to IDL which is quickly converted to LDL
 The cholesterol-rich LDL is cleared from the plasma primarily by the
liver which expresses the LDL receptor, liver pulls it out of circulation
 Cholesterol makes membranes -> taken up, broken down, converted to
IDL, quickly goes to LDL
 Loss of a functional LDL receptor results in an increased circulating
plasma cholesterol level
 Build up of excess cholesterol can lead to formation of xanthomas and
atherosclerotic plaques
o Loose a receptor -> take up less LDL -> cholesterol build up in
blood
o Oxidized version forms plaques
 Normally the LDL receptor binds the LDL particle, internalizes, releases
the LDL and recycles back to the plasma membrane to bind another one
 The cholesterol is metabolized in the cell for multiple purposes and can
actually regulate receptor synthesis (downregulate), cholesterol synthesis
(downregulate), and cholesterol storage (upregulate)
 Normal -> doesn’t happen if muatations no down regulating and keeps
making and secreting cholesterol, not taking enough
 When take up cholesterol -> downregulate receptor synthesis, and
synthesis of cholesterol in liver -> halts endogenous production of
cholesterol -> increases stored cholesterol
 Mutations of LDL Receptor
o No receptor made
o No receptor makes it to the membrane
o Poor or no binding
o No internalization
o No recycling (least serious)
Autosomal Recessive Disorders
BHS 116 - Physiology
Notetaker: Jessica Kulick
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Date: 10/12/2012, 2nd hour
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Largest category of Mendelian disorders
Cystic fibrosis, α1-antitrypsin, sickle cell anemia, glycogen storage disorders
Result only when both alleles at a gene locus are mutant (homozygous)
 One copy = don’t have disease, only a carrier
 Both copies = affected
Trait normally doesn’t effect parents but siblings affected 1 in 4
Complete penetrance is common
 Penetrance is the expression (symptoms) of a trait (2 mutant copies)
Age of onset is frequently early in life because both copies of a gene are knocked
out
2 carriers as parents that don’t have the disease
 25% chance of offspring affected -> both mutant copy
 50% chance of being a carrier
 25% chance f not having any copies of the mutant gene
Because a carrier can be an asymptomatic heterozygote, several generations may
pass before the descendants of the individual mate with another heterozygote and
produce affected offspring
 Need 2 carriers or 1 affected and 1 carrier to pass on the disease
Frequently involve enzyme gene expression
 Include almost all f the inborn errors of metabolism
 Only one copy of enzyme will still be fine
The biochemical consequences of an enzyme defect may lead to some major
consequences
 Accumulation of substrate, intermediates, and/or metabolites
o Knock out enzyme 1 = accumulation of intermediate 1
 Can lead to decreased amount of end product
o Might be the important thing
 Failure to inactivate a tissue damaging substrate
o Liver -> accumulation of a toxic substance or substrate
Glycogen storage diseases (glycogenoses)
 Most glycogenoses are inherited as autosomal recessive
 Characterized as a deficiency in any one of the enzymes involved in
glycogen synthesis or degradation resulting in excessive accumulation
glycogen or some abnormal form of glycogen in various tissues
o Typically glycogen degradation
 The type of glycogen stored, its intracellular location and tissue
distribution of the affected cells vary depending on the specific enzyme
deficiency
 2 major forms and 1 minor form
o Hepatic forms (liver)
o Myopathic forms (skeletal muscle)
o Glycogen storage diseases associated with acid maltase (in the
lysozyme) deficiency and lack of branching enzyme
 Glycogenoses have traditionally been divided into a dozen or so
syndromes designated by Roman numerals
 Hepatic Forms
o Deficiency in hepatic enzymes involved in glycogen metabolism
lead not only to the storage of glycogen, but can also lead to
hypoglycemia (von Gierke Disease, type I)
Date: 10/12/2012, 2nd hour
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BHS 116 - Physiology
Notetaker: Jessica Kulick
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Hepatic enlargement and hypoglycemia are the predominant
clinical signs
o Mutation prevents glucose breakdown in liver -> builds up ->
hypoglycemia -> enlarged liver because of glycogen stores ->
less glucose circulating
 Myopathic forms
o In the skeletal muscle, glycogen is used as an energy source
 Highly metabolic so need to make ATP
o Deficiency in glycolytic enzymes leads to glycogen storage and
is associated with muscle weakness (McArdle Disease, type V)
 Decrease glycolysis
 Once ATP and phosphocreatine used up -> run out of
energy
o Patients present with muscle cramps after exercise and lack of
exercise-induced rise in blood lactate levels due to blocked
glycolysis
Clicker: Regarding autosomal recessive inheritance, if a homozygous healthy male mates with a
heterozygous female carrier, how likely is their child to be homozygous recessive diseased? 0%