Genetic Basis of Disease (PATHO #2)

gene

fundamental unit of DNA

changes in DNA can be linked to diseases

epigenetic changes

alterations in gene expression due to enviormental stressors, behaviors, or lifestyle

pharmacogenomics

gene function in health, disease, and responses to medications

genetic

study of inheritaed traits

genomics

study of interation of all genetic material (not only genes)

deoxyribonucleic acid (DNA)

double-helical structure of nucleotides

nucleotide

pentose sugar

phosphate

purine or pyrimidine nitrogen base

nitrogen bases

dna: adenine, thymine, guanine, cytosine

A-T and C-G pairing

RNA: uracil replaces thymine

gene

nucleotide sequence

basic unit of heredity

exons, introns, codon

exons

portions of genome that encodes protein

introns

portion of genome that doesnt code for protein

codon

set of three nucelotides that signal a specific amino acid

gene mutation

dmaage or change to a gene that alters genetic code

• May be inherited or occur sporadically

• Point and frameshift mutations

germ cell mutation

gamates affected: may b passed to offspring

somatic cell mutation

body cells, not passed to offspring

gene nomenclature

names- some genes have specidic names e.g BRCA1 (breast cancer type1)

location- gene locus chromosome number, arm and region

short arm: p

long arm: q

further divided inro regions bands, subandsb

centromere for gene nomenclature

Junction

Between p and q arms

• Cystic fibrosis: 7q31.2

• BRCA1: 17q21

• BRCA2: 13q12-q13

human karyotype

picture of chromosome pairs

humans: 23 pairs

autosomes

1st 22 pairs

sex

23rd pair

female xx

xy male

y chrosome smaller than x

Chromosomal abnormalities

• Down syndrome

• Trisomy 21

• 3 copies chromosome 21

Gene Expression

Transcription and translation

Transcription

• DNA to mRNA (messenger RNA)

• RNA polymerase uses DNA as template to form mRNA strand

• Splicesosomes

  • Excise introns

• mRNA leaves nucleus

Translation

• mRNA to protein

• Ribosome

  • mRNA transcript “read”

• tRNA (transfer RNA)

  • One end binds to 3-nucleotide sequence on mRNA

  • Other end contains corresponding amino acid for the nucleotide sequence

• Amino acids linked by peptide bonds

Regulating Gene Expression

• All cells contain the same genes

• Expression and rate of expression varies between cells

• Enhancers and silencers

  • Transcription factor binding sites on DNA that affect DNA transcription rates

Inheritance Patterns

allele, genotype, phenotype

allele

gene inherited from one parent

genotype

genetic code

phenotype

physical expression of the genes

Heterozygous

inhertance pattern

alleles carry diff traits

Homozygous

inheritance pattern

Alleles carry same traits

Dominant trait

inheritance pattern

One allele needed for expression

Represented capital letter

Recessive trait

inheritance pattern

Two alleles needed for expression

Represented by lower case letter

Carrier

inheritance pattern

Heterozygous for recessive trait

Mendelian Inheritance

inheritance pattern

• One copy of a gene is inherited from each parent

• Punnett square

autosomal traits

inheritance pattern

• One copy of dominant allele needed for expression

• Two copies of recessive allele needed for expression

Sex-Linked Inheritance (AKA X-linked) males

46 XY

Sex-Linked Inheritance (AKA X-linked) Females

46 XX

hemophilia

• X chromosome larger than Y chromosome

  • Some genes, no corresponding allele on Y chromosome

  • Allele on X chromosome expressed

    • Regardless if dominant or recessive

Genetic penetrance

• Ratio of people with phenotype compared to genotype

• High penetrance indicates almost all individuals with the gene express phenotype

• Example: BRCA1 has 85% penetrance

Genetic expressivity

Related to severity of genetic disorder

• May vary for a given condition

• Example: Marfan’s syndrome

Complex (Multifactorial) Inheritance

• Combination of one or more genes plus environmental triggers

  • Majority of diseases have this pattern

  • Examples: hypertension, diabetes mellitus, cancer

Single-Nucleotide Polymorphisms (SNP’s)

• Changes in one nucleotide of a gene sequence

  • Example: AACGT vs ATCGT

• Can have profound effects if improper amino acid coded

  • Example: sickle cell anemia

Mitochondrial DNA

• Inherited from the mother (maternity testing)

• Can be damaged by free radicals

  • Lacks the repair process of DNA found in nucleus

    • Damage implicated in diseases such as diabetes, cancer, and heart failure

• Disorders can be inherited: neurodegenerative disorders, hypertrophic cardiomyopathy

  • Defective mitochondrial DNA can be replaced with normal mitochondrial DNA

CRISPR

• Clustered Regulatory Interspaced Short Palindromic Repeats

  • Gene “editing” in embryonic development

  • Highly controversial

Pharmacogenomics

• Interaction between a person’s genetics and medications

• Examples:

  • Slow acetylator phenotype

  • Warfarin (Coumadin) response

  • Pharmacological management of hypertension in individuals of African ancestry

Proto-oncogene

• Normal genes that control cell proliferation

• Mutation leads to activate oncogene

Oncogene

Enables uncontrolled cell proliferation

• Direct synthesis of oncoproteins

• Viral insertion of an oncogene may also occur

  • Example: human papillomavirus leading to cancer

Oncoproteins

• Regulate cell cycle, produced from oncogenes

• Direct cell to undergo uncontrolled proliferation

• Defects leading to oncogene and oncoprotein formation increase cancer risk

Tumor suppressor genes

• Inhibit uncontrolled cell proliferation

• p53 tumor suppressor gene stops mitosis

• p53 mutation may lead to uncontrolled cell growth

Knudson’s “Two Hit” Hypothesis

• Alfred Knudson proposed “two hit” hypothesis for cancer development

  • Both alleles must be damaged

  • “First hit”

    • Initial hereditary allele mutation

  • “Second hit”

    • Mutation or damage to other allele

• Holds primarily true unless a disease is autosomal dominant

Chromosomal Alterations

aneuploidy, translocation, deletion

aneuploidy

• Different number of chromosomes than 46

• Examples: Trisomy 21; Turner syndrome (45, XO)

translocation

One piece of a chromosome breaking off and joining another

deletion

peice of chromesome is broken off and lost

Epigenetics

• Behaviors, lifestyle, and environmental factors

  • Do not change DNA sequence

  • Change the way DNA is “read”

• Reversible changes

• Turn genes “on” or “off”

• Examples of changes:

  • DNA methylation

  • Histone modification

  • Non-coding RNA

Genetic Assessment

• Pedigree (genogram)

  • Multigeneration history

• Karyotyping

• Polymerase chain reaction (PCR)

• Fluorescence in situ hybridization (FISH)

• Southern blotting

Prenatal Screening

• Women 35 years or older

• Abnormal ultrasound findings

• Couples who are close blood relatives

• Women who have a condition associated with increased risk of fetal problems

• Unexplained or multiple miscarriages

• Family history of an inherited condition, intellectual disability, or birth defects

Maternal serum screening (Prenatal Diagnosis of Genetic Disorders)

Proteins from the placenta and fetus enter maternal circulation

(Prenatal Diagnosis of Genetic Disorders) Chorionic villus sampling

Usually for women age 35 years or older

Performed between 10 and 12 weeks of pregnancy

(Prenatal Diagnosis of Genetic Disorders) Amniocentesis

Diagnose fetal chromosome problems

Performed on amniotic fluid between 16 and 18 weeks of pregnancy

(Prenatal Diagnosis of Genetic Disorders) Percutaneous umbilical cord blood sampling

Also called cordocentesis

Examines fetal umbilical cord

Gene Therapy Ex vivo

• Genetically defective cells modified, and then readministered back to the patient

gene therapy In vivo

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• Directly delivers a normal copy of a specific defective gene into the target cells

• Germline vs somatic cell

Gene Therapy CRISPR-Cas9

• Clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9

• Nuclease that cuts the genome at the specific location to make needed edit in sequence

• Cell uses DNA repair machinery to proceed with making the desired change in the genome

Chimeric antigen receptor (CAR-T) gene therapy

• Patient T cells (immune cells) obtained and genetically modified

• T cells attack patient’s specific cancer cells

Ethical concerns gene therapy

• Patient counseling for genetic testing

• New area of health care, health-care professionals are exploring the best options

Familial hypercholesterolemia

Autosomal dominant

Lack of LDL receptors

Elevated cholesterol

Atherosclerosis

Genetic Disease

Familial adenomatous polyposis

Genetic Disease

Autosomal dominant

Adenomatous polyps in colon

Increased colon cancer risk

Colonoscopy screening from young age

Marfan’s syndrome

Autosomal dominant

genetic disease

Connective tissue disorder

Fibrillin-1 (FBN 1) gene mutation

Aorta, heart valves, lungs

Aortic rupture

Neurofibromatosis (NF)

• Autosomal dominant

• Two forms: NF1 and NF2

• Typical age of onset of symptoms is late teenage years

• Signs and symptoms: Café-au-lait spots, optic nerve tumor

Ehlers-Danlos Syndrome

• Diminished strength and integrity of skin, joints, and other connective tissues

• Patient must use caution with some types of physical activity

Cystic Fibrosis (CF)

• Autosomal recessive

• Most common lethal inherited disease in Caucasians

• Defect in cystic fibrosis transmembrane conductance regulator gene (CFTR), 7q31

• Disrupts lung function (excess mucus) and pancreatic secretions (malabsorption of nutrients)

• Newborns screened in U.S.

• Treatment:

  • Pancreatic enzyme supplements

  • Bronchodilators

  • Mucolytics

  • Nutritional supplements

• End-stage lung disease is the principal cause of death

Tay-Sachs disease

Lysosomal Storage Disease

Abnormal hexosaminidase A enzyme

Leading to ganglioside accumulation Death normally occurs by age 3

Niemann-Pick disease

Lysosomal Storage Disease

Deficiency in sphingomyelinase

Four types

Gaucher disease

Lysosomal Storage Disease

Autosomal recessive

Most common lysosomal storage disease

Accumulation of glucocerebrosides in macrophages and CNS

Wilson Disease

• Autosomal recessive

• Copper excretion is impaired

• Copper accumulates in liver and other organs

• Kayser-Fleisher rings in the eyes may be present

• Diagnosis based on measuring ceruloplasmin levels

• Chelating agents to clear copper

G6PD Deficiency

• X-linked, most common enzyme disorder

• Lack of glucose-6-phosphate dehydrogenase disrupts RBC functioning, hemolysis results

• Diagnosis with CBC and RBC smear

• Prevention of hemolysis is key

Klinefelter syndrome

Chromosomal Abnormalities

47, XXY

Decreased cognitive development

Testosterone replacement needed

Turner syndrome

Chromosomal Abnormalities

45, X0 karyotype

May result in spontaneous abortion

Variations in disease severity

Fragile X syndrome

Chromosomal Abnormalities

Disorder of X chromosome at Xq27.3

Characterized by long repeating sequences of CGG

Cognitive impairment

Down syndrome

Chromosomal Abnormalities

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• Most common chromosomal disorder

• Trisomy 21

• Wide variation of severity

• Flat facial profile, epicanthic folds around the eyes

• 80% have IQ of 25 to 50

• Prader-Willi syndrome

disruption of deletion of genes on chromesome 15 (paternal)

• hypothalamic dysfunction leading persons to overeat; hypotonia, low IQ, short stature, and hypogonadism

• Angelman’s syndrome

• neurological problems

Disruption or deletion of genes on chromosome 15 (maternal)

Huntington’s Disease

• Two forms of Huntington’s Disease, most common is the adult-onset

  • Autosomal dominant

  • Huntingtin protein (HTT) disrupted by trinucleotide repeats (CAG)

• No specific diagnostic imaging study

• No cure

• Clinical presentation includes a movement disorder, a cognitive disorder, and a         behavior disorder

Phenylketonuria (PKU) concept…

most newborns in developed countries are tested

Marfan’s syndrome concept…

Sudden hypotension may indicate aortic rupture

Familial hypercholesterolemia concept…

CVD in 1st-degree relative younger than 55 years is suggestive