Molecular Basis of

Genetic Diseases
Deniz Ağırbaşlı
 Learning Outcomes
By the end of this course you will be able to:
• classify groups of genetic diseases
(chromosomal-monogenic-polygenic)
• Classify mutations according to the effects on protein
function, giving examples
• define types of heterogeneity (genetic and phenotypic)
associated with genetic disease
• recall monogenic and polygenic disorders with examples
• explain general concepts of enzyme deficiencies
• describe the common diseases affecting enzyme, receptor,
transport and structural proteins
 Terminology
• hereditary = derived from parents
• familial = transmitted in the gametes through
generations
• congenital = present at birth (not always
genetically determined - e.g. congenital
syphilis, toxoplasmosis)
• ! not all genetical diseases are congenital - e.g.
Huntington disease - 3rd to 4th decade of life
 Classification
• 1. Disorders with multifactorial inheritance
(polygenic)
• 2. Monogenic (mendelian) disorders
• 3. Chromosomal aberrations
• 4. Mitochondrial

NB: Today distinctions are blurred !

• Some mutations are beneficial but most are
disasterous.
• Beneficial: antibiotic resistance (transposons)
• If a mutation occurs in
a) reproductive cells, the young may develop
abnormally or die
b) a body cell the mutant cells may multiply in an
uncontrolled way i.e. cancer
• A genetic disease occurs when an mutation in
the essential gene changes the amount or
function or both, of the gene product (mRNA
and protein).
Mutation Classification by the Effect on
Protein Function
• loss-of-function (most common)
e.g. Decreased amount normal protein:
Inborn errors of metabolism as in Tay-Sachs
• gain-of-function
e.g. Abnormal protein properties as in HD ,more copies of genes
in Trizomy 21
• novel property
e.g. HbS
• inappropriate expression
e.g. Hereditary persistence of fetal hemoglobin
e.g proto-oncogene normally promotes cell proliferation, but
causes cancer if it is abnormally expressed.
 Tay Sachs Disease
Autosomal recessive
•It is a loss of function mutation
•hexA gene is located on chromosome 15
•More than 50 Mutations are defined in Hex A gene (premature stop codon,
•defective mRNA splicing)
•Decreased amount and non functional Hexosaminidase A *
•Gangliosides accumulate in the brain becouse of non functional
hexosaminidase enzyme, mental functions are destroyed by the
accumulation of abnormal glycolipids.

Hexosaminidase enzyme activity in Tay-Sachs

 Huntington Disease
Autosomal Dominant
• It is a gain of function mutation
• HD gene has been identified on Chr4 encodes a protein of unknown function
(huntingtin).
• Huntington’s disease is caused by a polyglutamine [poly(Q)] repeat expansion in
the huntingtin protein.
• CAG codes for glutamine
• Excess glutamine agregates destroy neurons
No. of CAG Outcome
repeats
< Normal range; individual
28 will not develop HD
29-34 Individual will not develop HD
but the next generation is at risk
35-39 Some, but not all, individuals in this range
will develop HD; next generation is also at risk
> Individual will develop HD
40
• Expression of mutant huntingtin leads to
neuronal death, generalized brain atrophy,
changes in neurotransmitter level, neuronal
aggregates.
• The more the aggregates are, the earlier he
onset the symptoms appear.
 Sickle Cell Anemia (HbS)
Autosomal recessive
• Novel property
• Mutation on β globin chain of hemoglobin gene (chr 11)
• Valine is encoded instead of glutamine

Normal Disease
• Carriers (trait): Usually clinically normal,
under conditions of severe hypoxia, eg; in high
altitudes they show symptoms of SSD.
• Being a carrier is advantageous in malarial
region
• Patients(homozygotes): Decreased ability to
carry oxygen. RBC become rigid, inflexible.
• Clinic: pain episodes, strokes,organ damage
(lung, kidney, spleen) due to vessel occlusion
Genetics
▪ 2 copies of the gene
for Hb (each parent)

▪ HbS –Recessive
▪ S=Sickle
▪ A=Normal
 Hereditary persistence of fetal
hemoglobin
• It is a mutation associated with ectopic (or
inappropriate) gene expression
• The majority of healthy adults have <1 % Hb F.
• HbF(2α2γ), adult hemoglobin HbA(2α2β)
• HPFH results from mutations within the β-globin
gene cluster that alter normal hemoglobin
switching.
• Elevated Hb F has no clinical significance in
healthy individuals; however, HPFH can be
beneficial in patients with sickle cell disease or
beta thalassemia, as increased Hb F leads to
milder phenotypes.
 The relation of genotype and
phenotype in genetic diseases
• Heterogeneity: State of having different
characteristics within a group.
• Phenotype" is the visible or quantifiable effect
of the expression of a gene, whereas the
specific genetic constitution responsible for a
phenotype is called "genotype
 Locus heterogeneity
• One disease, multiple loci
• For example, different genes that influence breast
cancer susceptibility have been found on
chromosomes 6, 11, 13, 14, 15, 17, and 22.
• Inheritance patterns may differ for different loci
• Hereditary deafness > ~ 50 loci mapped
• large number of different loci with recessive,
dominant, X-linked and polygenic forms of the
disorder
 Allelic heterogeneity
• One disease, one locus, multiple alleles
• Example: Phenyl alanine hydroxylase
mutations in PKU
 Phenotypic heterogeneity
• 1. One gene, many mutations, many phenotypes:
becouse of allelic heterogeneity
• 2. One gene, one mutation, many phenotypes:
becouse of variable expressivity, pleiotropy, reduced
penetrance, epigenetics, mosaisicm, environmental
effects.
• Prasun P, et al.JPGM,2007;53:257-261
 Phenylketonuria (PKU)
An Example of Allelic and Locus Heterogeneity
• Autosomal reccesive
• Metabolic disease that results in mental retardation
and other neurological problems when treatment is
not started within the first few weeks of life. .

Phenylalanine hydroxilase
Phenylketonuria cont.

Newborn screening is important

We can conserve mental
development with low Phe Ala diet
 Changes of Enzyme /Changes in Enzyme
inhibitor
1.mutations leading to reduced amount of
Molecular Basis hexosaminidase causing Tay-Sachs
Of Diseases 2.mutations that impair secretion from liver to
serum causing Emphysema and Liver disease:
α1-Antitrypsin deficiency
3. Phenylketonuria
Neurodegenerativ -Changes of a receptor
e e.g. Low density lipoprotein receptor
diseases Deletion or point mutation that reduce synthesis,
Huntington, Or transport to the cell surface or binding to low
Alzheimer etc. density lipoprotein
Causing Familial hypercholesterolemia
Change of a transport or carrier protein
1.e.g. Haemoglobin
Changes in structural Mutations in splice sites (commonest) leading to
Proteins Reduced β-globin causing β-Thalassemia, in
1. reduced normal collagen α-Thalassemia the α-globin gene is usually
or,mutant collagen: deleted
Osteogenesis imperfecta 2.e.g. Cystic fibrosis transmembrane conductance
2. Fibrillin mutations causing Regulator. Deletions or point mutation causing
Marfan syndrome Cystic fibrosis.
3.deletion of dystrophin gene:
Duchene muscular Dystrophy
 General Concepts of Enzyme
Deficiencies
• 1. Most enzyme deficiencies are recessive
• 2. Substrate accumulation or product
deficiency
• 3. Diffusable vs macromolecular substrates
• 4. Loss of multiple enzyme activities (common
subunit, cofactor)

• 5. Phenotypic homology (enzymes of same metabolic pathway)

 Changes in Enzyme inhibitor
α-1 Antitripsin deficiency
• Autosomal codominant
• SERPINA gene in α 1-AT locus on Chr 14 inhibits elastase in
lungs. When there is a deficiency in the enzyme, the excess
amount of elastase allows progressive degradation of elastin
in alveolar walls
• Abnormal folded protein cannot enter the circulation and
accumulates in liver cells.
Alpha1 antitrypsin deficiency
(protease inhibitor def)
⚫ AAT, specified by the protease inhibitor (PI) locus is the
major plasma protease inhibitor of leucocyte elastase
(protease) that play a role in development of emphysema
PI locus is polymorphic
⚫ M:normal AAT levels
⚫ S: mildly reduced AAT levels
⚫ Z severly reduced AAT levels (have 15% of normal plasma
AAT)
⚫ We call the severe form ZZ
⚫ Even among ZZ individuals, substantial variability in lung
function is observed, suggesting that genetic modifiers
may influence the expression of lung disease in severe AAT
deficiency..
 Change in receptor
Familial Hypercholesterolemia
• Autosomal dominant
• LDLR gene is located on
chromosome 19
• More than 700 mutations are
identified on LDL receptor
gene
• LDL is bad cholesterol. Thus, the more
LDL-cholesterol you have in your blood, the
greater is your risk of heart disease.
• The receptor which takes the LDL to the cells
are defective and LDL stays in circulation.
Agregates and causes atherothrombosis.
Cholesterol agregates in skin, vessels and
tendons.
Agirbasli D, et al. Journal of Clinical Lipidology 2018;12:863-867
 Change in structural proteins
Marfan Syndrome
• FBN1 gene is located on chromosome 15
• Autosomal dominant
• fibrillin - secreted by fibroblasts, essential for the
formation of elastic fibers found in the connective
tissues.
• mutant/ abnormal fibrillin is synthesized
• Mutant fibrillin inhibits the functions of normal
fibrillin so the pathogenesis is called DOMINANT
NEGATIVE
• They are often more deleterious than mutations
causing the production of no gene product (null
mutations or null alleles).
Marfan Syndrome-2
 Change in structural proteins
Duchenne Muscular dystrophy
• The DMD gene is located on the X chromosome.
• The DMD gene encodes for the protein
dystrophin, found in muscle cells and some
neurons.
• It occurs mostly in young boys
• It first affects the muscles of the pelvis, upper
arms and upper legs,
• In terminal state, smooth and cardiac muscles are
affected
Gower’s sign in DMD
 Change in transport / carrier protein
Cystic Fibrosis
• CFTR (cystic fibrosis transmembrane conductance regulator)
gene on Chr 7 is responsible, autosomal recessive
• Cause: deletion of only 3 bases on chromosome 7
• defect in the transport of chloride ions across epithelia
–electrolyte balance is defected
• Mucus is thick and and sticky,
it blocks the tubes, ducts etc.
• Sweat becomes salty
• DIAGNOSTIC: sweat test

• CF mostly affects the lungs, pancreas,

liver, intestines, sinuses, and sex organs
• The CFTR protein has different roles in different
types of epithelial cells. Normally, this protein
allows chloride ions to exit the mucus-producing
cells. After chloride leaves the cells, water follows
and thins the mucus. However, if the CFTR protein
has been damaged, as in cystic fibrosis, the
chloride ions are not allowed out of the
mucus-producing cells. As a result, the mucus
thickens and becomes sticky and obstructs the
various pathways. This obstructive process also
prevents bacteria from being cleared from the
cells and thus increases the potential for infection
 Cystic Fibrosis

"Woe is the child who tastes salty from a kiss on the

brow, for he is cursed, and soon must die.“
-Northern European Folklore
 Thalassemia

• Hemoglobin is the oxygen

carrier in vertebrate red blood
cells.
• The molecule contains four
subunits
• 2 α , 2 βglobin chains
• Each subunit composed of
polypeptide chain globin and
prostetic group heme.
• Heme is a iron containing
pigment that combines with
oxygen to give the molecule its
Oxygen transport ability
 β thalassemias

• Decreased β globin production causes anemia.

• Imbalance in globin synthesis leads to precipitation of
excess α chains, leads damage of erytocyte
membrane.
• β chain is important in post natal period. Onset of β
thalassemia apperent untill a few monts after birth (β
globin replaces γ ).
• Synthesis of Hb A reduces. (α2β2)