Transcript 09. Gene diseases of human

Theme: Gene diseases
of human
Lecturer: ass. prof. Tеtyana Bihunyak
The main questions:
1. Gene mutations
2. Gene diseases (metabolic
disorders or molecular pathology)
2.1. Autosomal disorders
2.2. Sex-linked disorders
3. Indications for prenatal genetic
counseling
Single Gene disorders
In 1966 about 1500 single gene
disorders known.
By 2012 over 6000 identified.
There are between 50000-100000
structural genes so more
disorders likely to be identified.
Single gene (monogenic or mendelian) disorders 24/1000 live births (2.4%)
12 670 monogenic traits and diseases (incl.
subtypes).
For 9288 gene or its chromosomal location is known.
971 with a known molecular defect
1. Autosomal dominant disorders - 15/1000
Examples: Familial hypercholesterolaemia,
brachydactylia
2. Autosomal recessive disorders – 7.5/1000
Examples: Cystic fibrosis, phenylketonuria,
hydrocephalus, albinism
3. X-linked disorders (dominant and recessive) 1.5/1000
Examples: haemophylia, hypophosphataemia
4. Holandric disorders
Gene disorders (metabolic
disorders) or molecular
pathology are caused
by mutation in the genes
A gene mutation or point
mutation (since it applies to a
particular gene locus) is the result of
a change in the nucleotide
sequence of the DNA molecule in a
particular region of the chromosome
These mutations take the form of the
duplication, insertion, deletion, inversion
or substitution of bases.
Such a change in the base sequence of
the gene is transmitted to mRNA during
transcription and may result in a change in
the amino acid sequence of the
polypeptide chain (modified polypeptide)
produced from it during translation at the
ribosomes
Gene mutations occurring
during gamete formation are
transmitted to all the cells of the
offspring and may be significant
for the future of the species.
Somatic gene mutations
which arise in the organism are
inherited only by those cells
derived from the mutant cells by
mitosis.
Task
In some regions of South Africa there is a
spread sickle-shaped cell anemia, in which
erythrocytes have shape of a sickle as a result
of substitution of glutamine by valine in the
hemoglobin molecule. What is the cause of
this disease?
A.
B.
C.
D.
E.
Transduction
Gene mutation
Genomic mutations
Crossin-over
Disturbance of mechanisms of genetic
information realisation
Genealogy method (Pedigree Analysis)
Autosomal-Dominant inheritance:
1) a trait can effect both sexes (female and
male can be ill);
2) the trait is inherited vertically in the
pedigree (it affects every generation);
3) one or both parents of ill child are ill
Autosomal dominant disorders
N Mating types
AA
Aa
aa
Risk for progeny
1.*Aa x aa
0
1/2
1/2
1/2
2. Aa x Aa
1/4
1/2
1/4
3/4
3. AA x aa
0
1
0
1
4. AA x Aa
1/2
1/2
0
1
5. AA x AA
1
0
0
1
Affected individuals are underlined.
* - the most often mating type
Autosomal dominant disorders. Pedigree.
I
1
2
II
1
III
1
2
2
3
4
5
3
4
6
7
5
8
9
6
7
10
11
IV
1
2
3
4
5
8
12
6
Brachydactylia (Aa)
(shortness of the
fingers or toes)
Familial hypercholesterolaemia (FH)
FH accounts for 5% of the coronary artery
disease (CAD) seen in the Western world
Heterozygotes (Aa) 1:500
Homozygotes (AA) 1:1.000.000
The most frequent type of monogenic
hypercholesterolaemia
Mutation in the gene coding for the lowdensity lipoprotein (LDL) receptor
The LDL receptor gene maps to chromosome
19p13 and is made up of 18 exons
The mature mRNA codes for a protein of 839
amino acids
Diagnosis:
1. Clinical symptoms:
premature
atherosclerosis,
xanthomatosis (fatty
deposits occur in various
parts of the body).
Variability in the age of
onset (majority - in
third or fourth decade).
2. Family history.
3. Biochemical findings
Increased fasting total
cholesterol.
4. DNA analysis.
Achondroplasia. Autosomal dominant trait, occur with a
frequency of 20/1.000.000. Affected persons are
characterized by a peculiar form of dwarfism with short
limbs, an enlarged head, small face and depressed nasal
bridge. The trunk is normal in size, but lordosis occurs
Collagen gene mutation
null
mutation
NORMAL
TYPICAL
TYPE I OI
2n
n
dominant negative
mutation
TYPICAL
TYPE II OI
a1
n normal chains + n mutant chains
a2
n / 4 procollagen molecules
PROCOLLAGEN
n procollagen
molecules
n / 2 procollagen molecules
DEGRADED
Prognathism
is the positional relationship of the
mandible to the skeletal base where
the jaw protrudes beyond a
predetermined imaginary line in the
coronal plane of the skull.
The word prognathism derives from
Greek pro (forward) and gnathos
(jaw). An individual's top teeth and
lower teeth do not align properly.
It is incompletely penetrant
autosomal dominant trait
Progeria, or early aging,
is a rare autosomal dominant disorder that
apparently arises through new mutations.
Children affected by this
disorder start to show signs of
advanced aging when they are
only five or six. Their skin
wrinkles, their hair thins, they
start suffer arthritis, and their
blood vessels show
arteriosclerosis. Frequently,
affected youngsters die of heart
disease before they are 10
Autosomal-Recessive inheritance:
1) a trait can effect both sexes;
2) the trait is inherited horizontally in the
pedigree (it does not affect every generation);
3) parents of ill child can be healthy in the
phenotype, but they are heterozygous
(individuals who have affected children must
both be carriers)
Autosomal recessive disorders
N Mating types
1.* Aa x Aa
2. Aa x AA
3. AA x aa
4. Aa x aa
5. aa x aa
AA
1/4
1/2
0
0
0
Aa
1/2
1/2
1
1/2
0
aa
1/4
0
0
1/2
1
Affected individuals are underlined.
* - the most common mating type
Risk for
progeny
1/4
0
0
1/2
1
Pedigree of autosomal recessive disorder
I
II
III
IV
Affected
Consanguineous mating
Parental consanguinity (%) in AR pathology
Disease
%
Cystic fibrosis in Nothern Europe 1 – 2
Albinism
5
Phenylketonuria
12.5
Tay-Sachs disease
27
Alkaptonuria
60
Phenylketonuria (PKU)
•is an inherited error of metabolism caused
by a deficiency in the enzyme phenylalanine
hydroxylase.
•Loss of this enzyme results in organ
damage, unusual posture. It characterized by
mental retardation, hypopigmentation of hair
and skin, and mousy odor.
•PKU is an autosomal recessive disorder,
caused by mutations in both alleles of the
gene for phenylalanine hydroxylase (PAH),
found on chromosome 12.
•Diagnosis. Screening tests for all babies
•Treatment. Phenylalanine-low diet. Low
protein foods such as fruits, vegetables, and
some cereals are may be allowed.
Albinism
•is an autosomal recessive
disorder
•Lack of dark pigment melanin in
the skin, hair and eye
•It is caused by the absence of the
enzyme tyrosinase, which is
necessary for the synthesis of
melanine from typosine
Hydrocephalus an abnormal increase in
the amount of cerebrospinal fluid within the
ventricles of the brain. Hydrocephalus
makes the head enlarge. It cased by
obstruction to the outflow of cerebrospinal
fluid from the ventricles
Alkaptonuria
•Is an autosomal recessive disorder
• defect in the enzyme homogentisate
1,2-dioxygenase, which participates in
the degradation of tyrosine.
•Homogentisic acid and its oxide,
called alkapton, accumulate in the
blood and are excreted in urine in
large amounts (hence -uria).
•Pigmented the sclera of the eyes
(often only at a later age); the skin
darkened in sun-exposed areas; urine
may turn brown if collected and left
exposed to open air; kidney stones;
osteoarthritis and intervertebral discs
calcification
• Both blood plasma and urine can be
used for diagnosis (chromatography).
Tay-Sachs disease
•is an autosomal recessive disorder
•results from mutations in the HEXA gene on
human chromosome 15
•gangliosides accumulate in the brain's nerve cells,
leading to the premature death of the cells
•It characterized by infantile onset (3-6 months),
doll-like facies, cherry-red macular spot,
early blindness, deafness
•Death usually occurs before the age of four
•There is no known cure or treatment
Sickle cell anaemia in
humans is an example of base
substitution mutation affecting
a base in one of the genes
involved in the production of
haemoglobin
Hemoglobin and Sickle Cell Anemia
• Single base mutation in DNA
– A to T transversion
• Single amino acid change in the protein
– Glutamine to Valine
H 2N
H 2C
O
H 3C H CH 3
C
CH 2
C
H 2N H
O
C
H 2N H
O
OH
OH
Glutamine
Valine
Sickling Cells
Polymers of Normal
hemoglobin
deform red Sickle
blood cells
Sickle Cell Anemia
• Recessive trait
• Symptoms:
–
–
–
–
Chronic hemolytic anemia
Severe pain
Rapid septicemia (infection)
Asplenia (no spleen left)
How Was the Mutation Selected?
• Malaria
– Mosquito born plasmodium
parasite
– Some sickling is good
• Heterozygotes have the
advantage!
Task
Gene disease with characteristics:
dwarfism, large head, short limbs and
trunk, life span is normal:
A. Marfan Syndrome.
B. Achondroplasia.
C. Albinism.
D. Phenylketonuria.
E. Sicle-cell anaemia.
Idiogram of human X chromosome
Pseudoautosomal region 1 (PAR 1)
Steroid sulphatase
Kallmann’s syndrome
Dystrophin Duchenne’s muscular dystrophy
Becker’s muscular dystrophy
X-inactivation center (XIST)
HGPRT
Hemophilia B
G6PD, Hemophilia A
Pseudoautosomal region 2 (PAR 2)
Human X-recessive traits (in 10.000 males)
1. Red-green colour-blindness
800
Normal colour vision depends upon
the products of three loci – blue (BCP) on chr.7
and red (RCP) and green (GCP) in Xq28
2. Non-specific X-linked mental retardation
5
3. Duchenne muscular dystrophy
3
4. Becker muscular dystrophy
0.5
5. Haemophilia A (factor VIII deficiency)
Xq28. Recurrent haemorrhage
postoperatively and spontaneously into
soft tissues and joints
2
6. Haemophilia B (factor IX deficiency)
s. Christmas disease Xq27.1
0.3
7. X-linked ichthyosis
2
8. X-linked agammglobulinaemia
0.1
X-Linked Recessive Inheritance
• Males show
disorder more than
females
• Son cannot inherit
disorder from his
father
Hemophilia. Hemarthroses (extravasation of blood into a joint or its
synovial cavity) It is caused by defect of the blood which prevents its
clotting due to deficiency of coagulation factors VIII (hemophilia A)
or IX (hemophilia B).
Task
A normal woman whose father had
hemophilia A marries a man who also
has hemophilia A. What is the chance
their son will have the disorder?
A.
B.
C.
D.
E.
100 %
50 %
75 %
25 %
0%
Duchenne muscular dystrophy (DMD)
Becker muscular dystrophy (BMD)
X – recessive disorder
A French neurologist Duchenne described a case in
1861. Becker muscular dystrophy (BMD) – a similar
but milder condition. Due to mutations in the same
gene. Frequency DMD 1: 3.500
BMD 1:20.000
Gene located in the X-chromosome – Xp21.
The DMD gene is one of the largest yet identified in
man. The gene contains at least 79 exons and is
expressed in muscle and in neurones of the cerebral
cortex.
The gene product – protein dystrophin. Dystrophin is
located at or close to the muscle membrane where it is
thought to act as a link between extracellular laminin and
intracellular actin.
1/3– new mutations, 2/3 – inherited cases (motherheterozygote).
DMD – deletions (2/3 cases) with a frameshift or
nonsense mutations. No synthesis of dystrophin or very
reduced.
BMD – 5-10% of normal dystrophin quantity. Deletion
without a frameshift or missense mutations.
Diagnosis - symptomatology, pedigree analysis, elevated
creatine kinase activity in serum, muscle biopsy,
electromyography, DNA diagnosis (incl. prenatal DNA
diagnosis).
Identification of heterozygotes – elevated creatine
kinase activity in serum (reveals 75% of Hz), pedigree
analysis, DNA analysis.
Schematic representation of the probable structure of
the dystrophin protein molecule which is depicted as a
dimer linking intra-cellular actin with extra-cellular
laminin
Extracellular
laminin
6 glycoprotein complex
Muscle
membrane
Dystrophin dimer
Intracellular
actin
X-Linked Dominant inheritance:
1) a trait affects mostly females;
2) an affected male passes the trait to all his
daughters
X-linked dominant disorders
Affected individuals are underlined *
- the most common mating types
XaY
Risk for
progeny
1/4
1/4
1/2
0
1/2
0
1
1/2
0
0
1/2
1/2
XAXA
XAXa
1.* XAXa x XaY
0
1/4
1/4
XAXA x XaY
0
1/2
3.* XaXa x XAY
0
Nr.
2.
Mating types
XaXa XAY
4.
XAXa x XAY
1/4
1/4
0
1/4
1/4
3/4
5.
XAXA x XAY
1/2
0
0
1/2
0
1
Human X- dominant diseases
Vitamin D resistant rickets
s. Familial hypophosphataemic rickets
s. Hypophosphataemia.
1 / 20 000.
Failure of the intestinal epithelium to transport P.
Growth retardation. Childhood rickets. Reduced
serum phosphate.
Gingival sinuses. Delayed eruption of teeth. Skull
abnormalities. Both primary and secondary teeth
involved. High pulp horns.
Hypophosphatemia (Vitamin D-resistant rickets)
Not enough calcium salts are deposited in the bones to make
them rigid: consequently they become soft and malformed
Pedigree of an X-dominant disorder
Enamel hypoplasia is hereditary defect that
cause holes and cracks to appear around the
crowns of the teeth. It is inherited as X-linked
dominant trait
Idiogram of human Y chromosome
Y genes (or gene families)
not found on the X and
active only in the testes SRY
Consequences
associated with
deletions of Y
segments
Short stature
PAR 1
Reduced
ability to
make
sperm
Y genes having
counterparts on the X
Centromere
Reduced ability
to make sperm
Area lacking
functional genes
PAR 2
* Housekeeping genes
** Genes that have X counterparts but are active
only in testes
PAR - “pseudoautosomal” regions
(1 and 2), able to swap DNA
(recombine) with the X
SRY - causes the testes to form
(sex determining region on the Y)
Y-Linked inheritance:
1) a trait affects only males;
2) father passes a trait to all sons
Holandric (Y-linked) inheritance
Hairy pinnae («hairy ears»)
Differences between Autosomal and Sex-Chromosomal
Disorders
Autosomal Disorders
Sex-Chromosomal Disorders
1. These arise by gene mutation in
sex chromosome (X).
1.These arise by gene mutation in
autosomes.
2. Mutated gene may be
dominant or recessive.
2. Mutated gene mostly is
recessive.
3. These disorders affect both the 3. These disorders affect the males
sexes equally.
more than the females.
4. Victim is homozygous or
heterozygous.
4. Victim (male) is hemizygous, as
has one X and one Y chromosome.
Prenatal Diagnosis
• Amniocentesis (1-2%)
– Amniotic fluid removed
• Chorionic villus sampling (0.3%)
– Cells from the chorion (surrounds amnion)
• Fetoscopy (2-10%)
– Direct visualization, removal of blood from
umbilical vein
Indications for prenatal genetic
counseling
• Mother 35 years old or older at time
of delivery
• Abnormal maternal serum screening
• Physical anomalies seen on
ultrasound
• Previous still birth, child died in
infancy
• Three or more miscarriages,
infertility
• Exposure during pregnancy
Indications for prenatal genetic counseling (cont)
• Family/personal history of genetic
condition, birth defect, learning problems
• Previous child with genetic condition, birth
defect, learning problem
• Parents are blood relatives
• Ethnic background