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Chapter 3: Genetic Basis of Disease

Terms in this set (60)

Family History = Genogram
Genomics
Is the study of the multiple genes of an organism and their interactions.
Pharmacogenomics
Is the study of how genes influence an individual's response to medications.
DNA
Double-helical structure composed of nucleotides.

Nucleotide

Nitrogen bases
Nucleotide
Pentose sugar, phosphate, purine or pyrimidine nitrogen base.
Nitrogen Bases
Adenine, thymine, guanine, cytosine ( A-T C-G).
Transcription DNA ---> RNA
DNA synthesizes RNA within the nucleus.

RNA = mirror image of a DNA strand

RNA = one strand

RNA nitrogen bases = adenine-uracil cytosine- guanine
Genes and Amino Acids
An average gene contains 3,000 nucleotide base pairs.

Within a gene, an arrangement of three specific nucleotide bases = codon.

Codon

An average ____ can code for 1,000 _____ _____.

Example: adenine-thymine-guanine = methionine
Codon
Contains directions for synthesis of a specific amino acid.
Mutation
Single nucleotide polymorphism (SNP) (called a point _______)

Defective gene (eg, BRCA1, BRCA2)

Defective whole chromosome (eg, trisomy 21)

Germ cell _______ = mutated gamete

Can be inherited or sporadic (environmentally induced).

Somatic cell

Germ cell
Germ Cell
Mutation can be inherited.
Somatic Cell
Mutation is not inherited.
Gene Locus
Labeling a ____: chromosome #, long arm (q) or short arm (p), region

Are sometimes given "nicknames" such as BRCA ____, which means breast cancer ____.

Example: Cystic fibrosis gene; 7q31.2 indicates the ____ is found on the long arm of chromosome 7 in the region numbered 31.2; nickname is CFTR ____.
What Is a Karyotype?
Appearance and number of chromosomes of an individual.
Chromosomes
23 pairs of chromatids= 46 __________

22 pairs are somatic cell __________ (called autosomes).

23rd pair includes the sex __________.

Structure = two chromatid strands connected by a centromere.

Corresponding genes on each chromatid = an allele.
Homozygous
Individual, both alleles on each corresponding chromosome are the same.
Heterozygous
Individual, the alleles on corresponding chromosomes are not the same.
Sex-Linked Traits
A female often carries a trait that the
male offspring expresses.

The Y chromosome does not have an equal number of genes as the X chromosome.

Some genes on the X chromosome are unopposed by an allele on the Y.
Hemophilia
Penetrance
Ratio of how many persons with the phenotype have the genotype.

Example: A gene is highly ________ if most people express a gene if they have it; for example, if a woman has the BRCA gene, there is an 85% chance of getting breast cancer; this gene is highly ________.
Expressivity
A disorder can be expressed more or less severely in different individuals.

Example: A person may have a gene for familial hypercholesterolemia but can have a mild or severe form of the disease.
Multifactorial Inheritance
A disease is caused by a combination of inherited susceptibility and environmental factors that trigger a disorder.

Diabetes or cancer is a _____________ genetic disease; a genetic susceptibility and environmental trigger cause this disorder.
Single Nucleotide Polymorphisms (SNP)
A mutation in one nucleotide of a gene sequence.

Nucleotide = pentose sugar, phosphate, purine, or pyrimidine nitrogen base.

Example: A normal nucleotide sequence may be ACTTG...but in the disease the nucleotide sequence is...ACTGG.
Mitochondria
Have their own ribosomes and DNA that regulate energy production.

They are theorized to be independent, bacteria-like organisms that became incorporated into human cells.

During fertilization, the ovum destroys the sperm ____________.

All ____________DNA is derived from the mother.

Maternity tests can be based on ____________l DNA.
Alteration in DNA
DNA __________ or mutations are changes in nucleotide sequences, as well as deletions or insertions of nucleotides.

These changes can represent the change of base sequences in a codon, leading to a change in the protein structure.

For example, a nucleotide base substitution results in a different amino acid being included in hemoglobin formation, leading to the development of sickle cell anemia.
Oncogenes: Cancer-Causing Genes
Activated _________ can be inherited or acquired.

When the cell that possesses this activated _________ undergoes transcription, the RNA will carry the defective message of the activated _________ onto the ribosomes.

The ribosomes, in turn, will synthesize defective proteins called oncoproteins.

These oncoproteins will direct the cell to undergo uncontrolled proliferation, persistent mitotic divisions, or persistent cancerous growth, which is why activated _________ can be considered cancer-causing genes.
Tumor Suppressor Gene
These genes inhibit uncontrolled cellular mitosis and lead to persistent proliferation.

An example is the p53 tumor suppressor gene, which stops the mitotic cell division cycle.

When defective, _____ __________ ____s do not suppress cancerous transformation of cells and cancer growth occurs uninhibited.
Cancer Caused by Virus
Another way that cancer occurs is through viral insertion of an oncogene.

For example, the human papilloma virus (HPV) inserts its DNA into the DNA of cervix cells.

When activated, this DNA stimulates the abnormal growth cycle associated with cancer cells.

Additionally, it inhibits the action of p53, a tumor suppressor gene.

This is the mechanism for the development of cervical cancer from HPV infection.
Knudson's "Two Hit" Hypothesis
Pairs of alleles make up an individual's genotype.

If one of the alleles of a pair becomes damaged or mutated, the normal corresponding allele can counteract the effect in most cases.

According to Knudson, the initial allelic mutation is the "first hit" in his theory.

In his investigations, he noted that cancer only developed in persons who acquired a second allelic mutation.

Persons who developed cancer possessed a hereditary mutation on one allele and acquired a second mutation on their normal allele sometime in the course of their lifetime... "two hits."
Aneuploidy
Abnormal number of chromosomes

Example: trisomy 21
Translocation
When one part of a chromosome breaks off and connects to another chromosome.
Mosaic
Occurs when there are cells with different numbers of chromosomes within the same individual.
Molecular Analysis
Acquired genetic alterations, inherited disorders, and infectious disease can be detected by:

Polymerase chain reaction (PCR)

Fluorescence in situ hybridization (FISH)

Southern blotting
Prenatal Diagnosis
Chorionic villus sampling (CVS) 10 to 12 weeks.

Amniocentesis 16 to 18 weeks
Ultrasound.

Percutaneous umbilical cord blood sampling (PUBS).
Who Should Be Offered Prenatal Screening?
Women 35 years or older who are pregnant or are planning to become pregnant.

Abnormal ultrasound findings.

Couples who are close blood relatives, such as first cousins.

Women who have a condition, such as diabetes, that can be associated with an increased risk of fetal problems.

Ethnicity

Unexplained or multiple miscarriages.

Family history of an inherited condition, intellectual disability, or birth defects.
Maternal Serum Screening
Proteins that are produced by the developing placenta and fetus enter the mother's blood:

AFP (alpha-fetoprotein)

hCG (human chorionic gonadotropin)

uE3 (unconjugated estriol)

DIA (dimeric inhibin A)

If a maternal serum screening test is positive, it indicates an increased chance for a fetal problem.
Gene Therapy
Viral vector

Liposome

Artificial chromosome under investigation.
Familial Hypercholesterolemia
Absent or dysfunctional LDL receptors.

Mutation at 19p gene locus.

Normally uptake of LDL by liver LDL receptors.

Liver lacks LDL receptors so liver does not have uptake of LDL and cholesterol manufacture is not suppressed.

Homozygous form of disease; severe total cholesterol levels 600 to 1,000 mg/dL.

Heterozygous form of disease; less severe; total cholesterol 200 to 400 mg/dL.

Early arteriosclerosis develops; early angina and MI.

Xanthoma and xanthelasma.
Familial Adenomatous Polyposis
Autosomal dominant condition.

Individual is born with APC allele and needs to have other allele mutate in order to develop disease.

Early onset of hundreds to thousands of adenomatous polyps throughout the colon.

Mutation at 5q21 = APC gene (defective tumor suppressor gene).

High risk of colon cancer.
Marfan Syndrome
Autosomal dominant disorder.

Connective tissue disorder.

Mutations in the fibrillin-1 (FBN1) gene on chromosome 15.

Abnormalities exist in the structural components of the aorta and heart valves, airways of the lung, suspensory ligament of the lens, dura mater of the spinal cord, and other connective tissues of the body.
Marfan Syndrome
Most common in males.

Tall stature with elongated arms and fingers.

Kyphoscoliosis

Ligament hypermobility of the hips, knees, ankles, arches, wrists, and fingers.

Heart murmur from aortic regurgitation or mitral prolapse.

Dysrhythmia

Aortic dissection

Burning sensation and numbness or weakness in the legs because of dura mater defects.

Joint pain (adult patients)

Dyspnea, severe palpitations, and substernal pain in severe pectus excavatum.

Spontaneous pneumothorax

Visual problems
Neurofibromatosis (NF)
Autosomal dominant

Mutated NF1 gene (tumor suppressor gene)

Mutated NP2 gene

Mutated 17q and 22q.

Gene that codes for the proteins neurofibromin and merlin are mutated.

Decreased production of these proteins results in various clinical features
"Elephant man" syndrome.
Neurofibromatosis (NF)
The clinical criteria used to diagnose __ are as follows:

Six or more café-au-lait spots (hyperpigmented macules)

Two or more typical __________ or one large _________.

Spinal cord and meningeal tumors.

Optic and acoustic nerve tumor.

Two or more tumors in the iris (Lisch nodules), often only identified by an ophthalmologist.

Long-bone abnormalities.

A first-degree relative (eg, mother, father, sister, brother) with __1.

Scoliosis

Bowed legs

Macrocephaly
Ehlers-Danlos Syndrome (EDS)
Abnormalities in the synthesis of collagen and other connective tissue proteins.

Skin is highly elastic and joints are hypermobile.

Easy bruising, poor wound healing, mitral valve prolapse (MVP), arterial aneurysms, arterial dissections, and occlusions.

The classic form of ___ occurs because of a mutation on the 9q34.2 and 9q34.3 genes, also called the COL3A1 and COL3A2 genes.
Cystic Fibrosis (CF)
Autosomal recessive disease caused by defects in the ______ ________transmembrane conductance regulator (__TR) gene.

__TR gene encodes for a protein that functions as a chloride channel and also regulates the flow of other ions across the surface of epithelial cells.

The __TR gene locus is 7q31.
__ chiefly involves the respiratory system and pancreas.

Thick mucous secretions form and block the lungs and pancreas.
Lysosomal Storage Disease
Are classified according to the accumulated substances, which include the sphingolipidoses, oligosaccharidoses, mucolipidoses, mucopolysaccharidoses (MPSs), lipoprotein storage disorders, lysosomal transport defects, and others.

Each __________ _______ _______ presents differently according to the undigested substance that accumulates within the cells and according to which major organ is affected.
Tay Sachs Disease
Lysosomal storage disease.

Mutation on chromosome 15
Deficiency of lysosomal enzyme: hexosaminidase A.

Ashkenazi Jews.

Ganglioside accumulates in the cells, particularly the central nervous system, causing progressive destruction of neurons and brain cells.
Tay Sachs Disease
Infants born with ___ _____ _______ appear normal until approximately 6 months of age.

As the infant matures, motor incoordination, lethargy, muscle flaccidity, and increasing cognitive impairment become apparent.

A characteristic that is diagnostic of ___ _____ _______ is a "cherry red spot" seen on the retina on ophthalmological examination.

Death usually occurs by age 3 years.
Prenatal diagnosis and carrier detection of ___ _____ _______ is possible.
Other Lysosomal Storage Diseases
Niemann-Pick disease

Gaucher disease
Wilson Disease
Abnormal copper metabolism.

Liver damage; cirrhosis.

Organs develop copper deposits.

Kayser-Fleischer rings visible in the eye.

Early symptoms include tremor, difficulty speaking, excessive salivation, ataxia, masklike faces, clumsiness with the hands, and personality changes.
Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
Is the most common enzyme disorder.

It is an X-linked inherited disease that primarily affects men.

RBCs undergo hemolysis under stresses
Symptoms: jaundice, yellowing of the skin and sclera.

Diagnosis: Heinz bodies, bite cells.
Klinefelter Syndrome
Males have a 47XXY karyotype.

Lack of development of the testes, gynecomastia, and skeletal and cardiovascular abnormalities occur.

Intellectual impairment also occurs.

Testosterone deficiency causes tall, lanky body proportions; sparse or absent facial, axillary, and pubic hair; decreased muscle mass and strength; feminine distribution of adipose tissue; decreased physical endurance; and osteoporosis.
Turner Syndrome
Missing X chromosome in the female so that karyotype is 45X.

Webbed neck, short stature, infertility, broad shield-shaped chest, small hips.

Cardiovascular problems, ovarian failure, hypothyroidism, visual problems.
Fragile X Syndrome
Second most common cause of genetically associated mental deficiencies after trisomy 21.

Defective Xq27.3 gene (also called the familial mental retardation [FMR] 1 gene).
Fragile X Syndrome
Autistic behavior

Hand flapping and avoidance of eye contact.

Shyness, sensory integration difficulties, attention deficits, hyperactivity, impulsivity.

Depressed affect

Anxiety

Learning disabilities

Aggressive tendencies

Mitral valve prolapse

Scoliosis

Craniofacial, genital, and musculoskeletal abnormalities.

Males have a long face with large mandible, large everted ears, and large testicles; hypermobile joints, high arched palate.
Down Syndrome
Trisomy 21

Diagnosed prenatally with amniocentesis, PUBS, CVS, and extraction of fetal cells from the maternal circulation.

1 in 50 births to mothers older than 45 years.
Down Syndrome
Flat facial profile.

Eyes oblique; palpebral fissures.

Epicanthic folds

80% of children have an IQ of 25 to 50. The remaining 20% have normal or near normal intelligence.

40% of children have congenital heart disease and esophageal and intestinal malformation.

10- to 20-fold increased risk of developing leukemia.

Weak immune system; susceptible to infection.

Adults susceptible to early Alzheimer's disease.
Prader-Willi Syndrome (PWS)
Also called Angelman syndrome.

Deletion or disruption of genes in the proximal arm of chromosome 15.

Hypothalamic dysfunction.

Severe obesity; constant hunger caused by dysfunction of the hypothalmus.

Hypotonia

Low IQ

Short stature

Hypogonadotropic hypogonadism

Strabismus

Small hands and feet

Ataxic gait

Behavioral problems

Seizures
Huntington Disease
Adult-onset, autosomal-dominant inherited disorder associated with degeneration of specific neurons in the basal ganglia and cortex.

Genetic defect at 4p16.3 called the __________ gene (also called HTT or HD gene).

The gene defect causes a part of DNA, called a CAG repeat sequence, to repeat many more times than it should and form the __________ protein.
Huntington Disease
Patients commonly develop symptoms in their mid-30s and 40s.

Chorea = movement disorder seen in HD
Initially, mild chorea causes dancelike movements or tics.

Severe chorea occurs later and can cause uncontrollable flailing of the extremities, termed ballism.

As the disease progresses, chorea is replaced by parkinsonian features, such as slowed up movements, muscle rigidity, and postural instability.

In advanced disease, patients develop an akinetic-rigid syndrome, without movement at all.

Other late features are spasticity, dysarthria, dysphagia, and slowed cognition to dementia, which occurs gradually.

Severe depression and suicidal ideation is common.
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