Mutation & Genetic
Disorders
JOHN PAUL E. SANTOS
University Science High School
Mutations
A mutation may be defined as a permanent
change in the DNA.
Mutations that affect the germ cells are transputted
to the progeny and may give rise to inherited
diseases.
Mutations thar aries in somatic cells are important
in the genesis of cancers and some congeital
malformations.
Mutations may
catagories:
be
classified
into
three
Genome mutations involve loss or gain of whole chromosomes
(giving rise to monosomy or trisomy)
Chromosome mutations result from rearrangement of genetic
material and give rise to visible structural changes in the
chromosome.
Gene mutations may result in partial or complete deletion of a gene
or, more often, affect a single base. For example, a single nucleotide
base may be substituted by
a different base, resulting in a point
mutation.
Autosomal dominant disorders (neurofibromatosis, tuberous
sclerosis, polycystic kidney disease, familiar polyposis coli,
hereditary spherocytosis, Marfan syndrome, osteogenesis
imperfecta, achondroplasia, familiar hypercholesterolemia)
Autosomal recessive disorders (cystic fibrosis, phenylketonuria,
homocystinuria,
hemochromatosis,
sickle
cell
anemia,
thalassemias, alkaptonuria, neurogenic muscular atrophies)
X-linked
disorders
deficiency)
(glucose-6-phosphate
dehydrogenase
Biochemical and molecular basis of singlegene disorders
1) Enzyme defects and their consequences
2) Defects in receptors and transport systems
3) Alterations in structure, function or
quantity of nonenzyme proteins
4) Genetically determined adverse reactions
to drugs.
Genetic Testing
Amniocentesis and Chronic Villi Sampling
Sample of amniotic fluid or placenta
Karyotyping
Taking a picture of the chromosomes in a cell
What Can Go Wrong?
Nondisjunction (most deadly)
Improper separation of homologous chromosomes
in meiosis I or chromatids in meiosis II or mitosis
(at an early embryonic stage)
Results in too many or too few chromosomes in
daughter cells
DNA mutations
More specific letter-changes in code
Results in the inability to make certain proteins
Nondisjunction Causes:
Aneuploidy: cells that have too many or too
few chromosomes are aneuploid.
Monosomy: only 1 of a pair present
Trisomy: 3 instead of 2 present
Disorders associated with defects in structural
proteins
Marfan syndrome
A disorder of the connective tissues of the body, manifested principally by
changes in the skeleton, eyes, and cardiovascular system.
Ehlers-Danlos syndromes
A clinically and genetically heterogeneous group of disorders that result
from some defect in collagen synthesis or structure (other disorders
resulting from mutations affecting collagen synthesis include osteogenesis
imperfecta, Alport syndrome, epidermolysis bullosa)
Disorders associated with defects in
receptor proteins
Familiar hypercholesterolemia
A disease that is the consequence of a mutation in the gene encoding the
receptor for low-density lipoprotein (LDL), which is involved in the transport
and metabolism cholesterol. More than 150 mutations, including insertions,
deletions, and missense and nonsense mutations, involving the LDL
receptor gene have been identified.
Disorders with multifactorial inheritance
Down Syndrome
Caused by Trisomy 21
Symptoms:
Mental retardation
Flattened face
Sparse, straight hair
Short stature
High risk of cardiac anomalies, leukemia,
cataracts, and digestive blockages
Average life expectancy: 55 years (much
longer than it used to be even just recently)
Edward Syndrome
Caused by Trisomy 18
Symptoms:
Mental and physical retardation
Skull and facial abnormalities
Defects in all organ systems
Poor muscle tone
Average life expectancy: 2-4 months
DiGeorge syndrome (chromosome 22q11 deletion a small deletion of
band 11 on the long arm of chromosome 22): Thymic hypoplasia, congenital
heart defects, abnormalities of the palate, facial dysmorphism, developmental
delay, and variable degrees of T-cell immunodeficiency and hypocalcemia.
Signs and symptoms
Patients with 22q11.2 DS usually have characteristic
facies. Common features include the following (see the
images below)[1] :
Retrognathia or micrognathia
Long face
High and broad nasal bridge
Narrow palpebral fissures
Small teeth
Asymmetrical crying face
Downturned mouth
Short philtrum
Low-set, malformed ears
Hypertelorism
Disorders with multifactorial inheritance
Klinefelter syndrome (XXY)
(2 or more X chomosomes
and
1
or
more
Y
chromosomes):
male
hypogonandism,
eunuchoid body habitus,
infertility,
cryptorchidism,
hypospadias,
skeletal
changes.
Jacobs Syndrome (XYY): Individuals are excessively tall,
may be susceptible to severe acne, the intelligence is in the
normal range, only 1-2% of individuals exhibit deviant
behavior.
Incidence unknown (lack of diagnosis)
Tall, acne issues, speech/reading problems
Disproportionate number incarcerated
96% are normal (most dont realize they
have this condition)
Turner syndrome (complete
partial monosomy of the
chromosome):
hypogonandism
phenotype,
with
or
X
female
short body,
webbing of neck,
heart anomalies,
infertility,
amenorrhea,
pigmented nevi,
peripheral lymphedema at birth.
Patau Syndrome
Caused by Trisomy 13
Symptoms:
Mental and physical retardation
Skull and facial abnormalities
Defects in all organ systems
Cleft lip & large triangular nose
Extra digits
Average life expectancy: 6 months
(but die in the first month)
Cri du Chat Syndrome (cry of the cat)
Deletion on part of chromosome 5
Fragile X
Repeated sequences of CCG on X chromosome
Normal = 6-50 copies
Carrier (males) = 50-230 copies
Disorder = more than 230 copies
Causes mental retardation (2nd behind only Down
Syndrome)
Autosomal Recessive Disorders
Cystic Fibrosis (CF)
Mutation on chromosome 7
Thick mucous develops in lungs and
digestive tract
Difficulty breathing & lung infections
Most common lethal genetic disorder
1 in 25 is a carrier
1 in 2500 has disorder
More Autosomal Recessive
Tay Sachs Disease
Fatty substance builds up in neurons
Gradual paralysis and loss of nervous function
by age 4-5
Single defective enzyme
Heterozygote carriers (Hh) do not have
disorder, but are resistant to Tuberculosis
Especially common in Jewish population
(central and eastern European descent), up to
11% are carriers
More Autosomal Recessive
PKU (Phenylketonuria)
Cant break down amino acid phenylalanine
(missing critical enzyme)
Phenylalanine builds up and interferes with nervous
system leading to mental retardation and even
death
Early screening phenylalanine restricted diet for
children with disorder
More Autosomal Recessive
Sickle-Cell Anemia
Abnormality in hemoglobin (carries oxygen in
our red blood cells)
Cells become sickle-shaped and clog blood
vessels (painful)
Causes poor circulation, jaundice, anemia, and
hemorrhaging
Heterozygote carriers (Hh) do not have
disorder and are resistant to malaria
8-10% of Africans (or descendants) are carriers
Sickle-Cell Anemia Photo
Autosomal Dominant Disorders
Neurofibromatosis (NF)
Could be Elephant Mans disorder
As mild as tan spots on skin
Could cause severe deformities,
tumors, even death
1 in 3000 newborns
Mutation on chromosome 17
Autosomal Dominant Disorders
Huntingtons Disease
Brain cells degenerate, causing involuntary
muscle jerks, slurred speach, loss of balance,
mood swings, memory loss, incapacitation
Progressive: eventually causes death
Onset: 35-45 years old
Repeated sequences of AGC on chromosome 4
Diagnostic test available, but no cure
Would you want to know?
X-Linked or Sex-Linked Traits
Traits located on X Chromosome
Males have them more often than females
They only have one X chromosome
X-Linked or Sex-Linked Traits
Colorblindness (3 types
Red/Green most common)
X-Linked or Sex-Linked Traits
Hemophilia
1 in 1500 males
Lack a blood clotting factor
Can bleed to death from wounds or
bruises (internal bleeding)
Duchenne Muscular Dystrophy
1 in 5000 males
Muscular deterioration starts 3-5 years
old
Wheelchair by 12, rarely survive past 20
