Patho chapter 6

Cellular Function: Genetic and Development Disorders

Genetic Diseases

• Can be genetic, environmental, or both.

Point Mutation

• Illustrates a point mutation where glutamic acid is replaced by valine.

Objectives

• General principles of development.
• Genetic and environmental causes of congenital disorders.
• Principles of diagnosis.
• Counseling in gene therapy.

Congenital Disorders

• Present at birth.
• Grouped according to genetic or environmental causes.
• Congenital malformations: errors in fetal development associated with structural defects.
• Teratogens: Environmental influences.

Principles of Inheritance: Gregor Mendel

• Documented a mechanism of inheritance through experiments with garden peas.

Mendel’s Model

1. Alternative versions of genes or alleles account for variations in inherited characters.
2. For each character (e.g., flower color), an organism inherits two alleles, one from each parent.
3. If two alleles at a locus are different:
   • One allele, the DOMINANT allele (R), determines the organism’s appearance or phenotype.
   • The other allele, the RECESSIVE allele (r), has no noticeable effect on the organism’s phenotype.
4. The Principle of Segregation:
   • The two alleles for a heritable character separate (segregate) during gamete formation and end up in different gametes.

Factors Contributing to Genetic Variation

• Independent assortment of chromosomes.
• Crossing over of non-sister chromatids.
• Random fertilization.
• Mutations: the original source of genetic variation.

Meiosis

• Meiosis reduces the number of chromosome sets from diploid to haploid.
• Meiosis is preceded by replication of chromosomes.
• Meiosis takes place in two sets of cell divisions, called meiosis I and meiosis II, resulting in four daughter cells.

Genetic Variation: Crossing Over

• Exchange of regions of non-sister chromatids.
• Important source of genetic variation.

Human Life Cycle

• Ovaries and testes produce haploid gametes by meiosis, resulting in one set of chromosomes in each gamete.
• Fertilization, the fusing of gametes, forms a diploid zygote which develops into an adult.

Karyotype

• A karyotype is a pictorial arrangement of all of an organism’s chromosomes.
• 22 pairs are called autosomes.
• 23rd pair are the sex chromosomes.

Sex Determination

• Human gender is determined by sex chromosomes.
  • Females: XX, homologous chromosomes.
  • Males: XY, not homologous chromosomes, but they behave so during meiosis.
• The presence of a Y chromosome confers male gender.

Punnett Squares

• Shows predictable patterns in transmission of single-gene traits from parents to offspring.

AA, Aa, aa represent possible genotypes with associated probabilities.

Codominance

• A and B alleles both display normal dominant-recessive relationships with the O allele.
• Neither A nor B is dominant over the other; A and B are Codominant.

Polygenic Inheritance

• Additive effect of two or more genes on a single phenotype.
• Often affected by environmental factors.
• Difficult to predict their occurrence.
• Example: human skin color. A range of genotypes (aabbcc to AABBCC) results in varying skin color phenotypes with fractions of progeny indicated.

DNA Mutation and Repair

• Mutation: permanent change in DNA structure.
  • Rare.
  • Potential mutagens: Radiation, Chemicals, Viruses.
• Single-stranded breaks are easily repaired.
• Double stranded breaks may result in permanent loss of genetic information at break point.

Two Types of Mutation

• Point mutation: Single base substitution.
• Frame shift mutation: Changes the genetic code dramatically.
  • Addition or removal of a base changes the reading frame.

Frame Shift

• Base-pair substitution can have no effect (silent), result in a missense mutation (different amino acid), or a nonsense mutation (stop codon).
• Base-pair insertion or deletion can cause a frameshift, leading to immediate nonsense or extensive missense.
• Insertion or deletion of 3 nucleotides doesn't cause frameshift but results in an extra or missing amino acid.

Genetic Disorders

• Apparent at birth or in later life.
• Majority inherited from parents; some from fetal development mutations.
• Divided into three groups:
  • Chromosomal aberrations.
  • Mendelian single-gene disorders.
  • Multifactorial or polygenetic disorders.
• Fourth group: single gene but doesn’t follow Mendelian pattern
  • Triplet-repeat mutations.
  • Mitochondrial mutations.
  • Mutations affected by genomic imprinting.

Chromosomal Abnormalities

• Errors in chromosome distribution during meiosis.
• Alterations of chromosome number can cause genetic disorders.
• Large-scale chromosomal alterations often lead to miscarriages or cause a variety of developmental disorders.

Aberrant Number of Chromosomes: Nondisjunction

• Failure of chromosomes to divide properly during anaphase.
• Anaphase lag: 1 chromosome left out of newly formed cell nucleus.

Results of Nondisjunction

• Aneuploidy: abnormal number of a particular chromosome, resulting from the fertilization of gametes in which nondisjunction occurred.
  • Trisomy: 3 copies of a particular chromosome.
  • Monosomy: only 1 copy of a particular chromosome.
  • Polyploidy: an organism has more than two complete sets of chromosomes.

Normal Chromosome Structure

• Normal Crossing Over
• Precise - No net loss of DNA

Abnormal Chromosome Structure

• Due to breakage, loss, or rearrangement of pieces of the chromosomes.
• Types: Translocations, Isochromosomes, Inversions, Deletions, Ring Chromosomes, Duplications.

Abnormality Brief Descriptions

• Reciprocal translocation
• Robertsonian
• Isochromosomes
• Inversion
• Deletion
• Duplication

Autosomal Chromosome Disorders: Trisomy 21

• Characterization: Extra chromosome 21, most common, associated with advanced maternal age. Rare form: 4% is translocation of the long arm of 21 to another chromosome.
• Trisomy 18 and 13: Less common and more severe. Average life expectancy a few weeks.
• Clinical Features

Autosomal Chromosome Disorders: Cri du Chat Syndrome

• Characterization: Deletion of short arm of chromosome 5.
• Clinical Features: Severe mental retardation, round face, congenital heart anomalies, Cry resembles a cat crying. Some live to adulthood and thrive better than those with trisomies.

Sex Chromosome Disorders: Klinefelter Syndrome

• 1:500-1:1000 live births.
• Extra X chromosome- XXY, XXXY, XXXXY.
• Clinical Features:
  • Infertility
  • Tall, long arms and legs
  • Breasts enlargements
  • High pitched voice
• Treatment: Testosterone therapy.

Turner Syndrome

• 1:3000 live births
• Monosomy X – X0 or Xx.
• Clinical Features:
  • Sterile
  • Short stature
  • Webbed neck
  • Ammenorrhea
• Treatment: growth hormone, estrogen replacement therapy.
• ~3% survive to birth

Mendelian Single-Gene Disorders

• Result from alterations or mutations of single genes.
• Affected genes may code for abnormal enzymes, structural or regulatory proteins.
• Classified according to:
  • Location of defective gene: Autosomal or sex chromosome.
  • Mode of transmission: Dominant or recessive. Pedigree Analysis

Autosomal Dominant Disorders

• Due to mutation of an autosomal dominant gene.
• Males/females equally affected.
• Usually 1 affected parent.
• Unaffected individuals do not transmit disease.

Autosomal Dominant Disorders: Marfan Syndrome

• Characterization:
  • Connective tissue disorder
  • FBN1 gene mutations (Fibrillin 1), chromosome 15
  • Dominant negative preventing assembly of normal microfibrils
• 1:5000 persons affected
• 70-85% familial
• Clinical Features:
  • Tall stature
  • Arachnodactyly
  • Cardiovascular lesions
  • Mitral valve prolapse
  • Bilateral dislocation of the lens
• Treatment:
  • TGFβ inhibitors
  • Beta blockers

Autosomal Dominant Disorders: Huntington Disease

• Characteristics:
  • Neurodegeneration
  • Localized to chromosome 4
  • Triplet repeats (CAG) -> Glutamine
• Morphology: Aggregates in the brain tissue
• Clinical Features: Involuntary movements of arms and legs
• Treatment: Tetrabenazine (suppresses jerking)

Autosomal Recessive Disorders

• Mutation of autosomal recessive gene.
• Males/females equally affected.
• Both parents carriers of mutant recessive gene.
• Unaffected individuals may transmit to offspring.

Autosomal Recessive Disorders: Cystic Fibrosis

• Characterization:
  • Abnormal ep. chloride channel protein
  • CFTR gene
  • Chromosome 7
  • Deletion of nucleotides that code of Phenylalanine
• 5% Caucasian Americans.
• 1:3200 live births
• Clinical Features: Thick secretions in glandular tissues. Bronchioles and pancreatic ducts primary affected.

Autosomal Recessive Disorders

• Albinism
  • Unable to synthesize tyrosinase
  • Risk for skin cancer, sun burn
• Phenylketonuria
  • Inborn error of metabolism
  • Excess phenylalanine
  • Mental retardation, seizures, severe irritability

Sex-linked disorders

• Alleles found on X or Y chromosome
• Recessive X-linked diseases usually occur in males
  • Females have two X chromosomes, so they usually have at least one normal allele
  • Only one X chromosome for males, so a single recessive allele will cause disease

Sex-linked disorders: Hemophilia A

• Characterization:
  • Deficiency in factor VIII
  • Inability to form fibrin clot
• Clinical Features:
  • Bleed easily and profusely from minor injuries
  • Hematoma

Nonmendelian single-gene disorders

• Does not follow classic Mendelian principles
• Categories:
  • Caused by long triplet repeat mutations, such as fragile X syndrome
  • Due to mitochondrial DNA mutations
  • Associated with genomic imprinting

Triple Repeat Mutations: Fragile X

• Characterization:
  • 2nd most common
  • 200-4000 repeats of sequence of CGG
  • Loss of function (silencing) of FMR I gene -> Familial Mental Retardation Protein
• Clinical Features:
  • Mental retardation
  • Abnormal facial features

Diagnosis, Counseling, and Gene Therapy: Prenatal Diagnosis and Counseling

• Maternal age >34 years
• Chromosomal disorder in previous pregnancy
• Known family history of x-linked disorders
• Known family history of inborn errors of metabolism
• Neural tube anomalies in previous pregnancy
• Known carrier for recessive genetic disorder

Diagnosis, Counseling, and Gene Therapy: Fetal Testing

• In amniocentesis, the liquid that bathes the fetus is removed and tested
• In chorionic villus sampling (CVS), a sample of the placenta is removed and tested
• Ultrasound and fetoscopy, allow fetal health to be assessed visually in utero

Diagnosis, Counseling, and Gene Therapy Genetic Analysis and Therapy

• Treat genetic disease by replacing defective gene with healthy gene Recombinant DNA Technology
  • PCR
  • Restriction enzymes
  • Electrophoresis
  • Sequencing
  • Nucleic acid hybridization
  • Genetic engineering