Genetic Basis of Disease

Question 1

Genetic Disease

Answer 1

Disease caused by defects in genes
Not all genetic diseases are congenital
Some only manifest in adulthood

Question 2

Heritable Disease

Answer 2

Diseases transmitted in the germline cells derived from one’s parents
Aka “familial”

Question 3

Congenital Disease

Answer 3

“born with”
Not always genetic (eg. can have congenital infectious disease)

Question 4

Veratrum californicum

Answer 4

(in sheep)
Ingestion of plant at days gestation:
13-14 = synophthalmia (cyclopia)
17-18 = motor nerve paralysis
12-30 = multiple defects
> 30 = hypoplastic metacarpus and metatarsus

Question 5

Mutagen

Answer 5

A physical or chemical agent which changes DNA resulting in an increased incidence of mutation

Question 6

Hyperkalemic Periodic Paralysis

Answer 6

Autosomal dominant inheritance
Sodium channel point mutation:
“leaky” channel leading to influx of K during hyperkalemia
Muscle becomes overly excitable and contracts involuntarily
Dietary changes, fasting, anesthesia, illness and exercise restriction can bring on attacks

Question 7

Genetic Defects

Answer 7

3 main types:
Single gene disorders
Chromosomal aberrations
Multiple genes

Question 8

Single Gene Disorders

Answer 8

Can involve somatic or germline cells
Involve mutations in DNA of a single gene

Question 9

Four types of single gene disorders

Answer 9

Silent
Missense
Nonsense
indels: Insertion–deletion mutations

Question 10

Silent mutation

Answer 10

still have same amino acids, will make same protein, no real change in phenotype… a base change did take place and there is mutation but we may never know it is there (nbd)

Question 11

Missense mutation

Answer 11

have a mutation that changes codon so now changing entirely different amino acid. may fold differntly, may not function at all, will change phentoype of animal.

Question 12

Nonsense

Answer 12

foolishness. encode a premature stop codon. end up allele that may not encode protein or a shortened one and may or may not be functional (happens often, won’t work).

Question 13

Frameshift Insertion

Answer 13

get an insertion of nucleotide so that codon sequence is thrown off and end up altering reading frame of gene, may end up with premature stop, encoding differnt amino acids, and a very differnt protein

Question 14

Frameshift deletion

Answer 14

lose a nucleotide, altered reading frame, encoding different amino acids

Question 15

Deletion, Non-frameshift

Answer 15

remove exactly 3 nucleotide. cutting a chunk out of the middle.

Question 16

Outcomes of Single Gene Mutations

Answer 16

Formation of abnormal protein
Reduction in synthesis of a protein
Formation of abnormal protein without impairing any steps in protein synthesis
Change in rate of synthesis, posttranslational processing, protein transport out of cell

Question 17

Point mutations

Answer 17

silence, missense, nonsense

Question 18

frameshift mutation

Answer 18

insertion, deletion

Question 19

Main Modes of Inheritance

Answer 19

Autosomal recessive
Autosomal dominant
X-linked

Question 20

Mechanisms of Single Gene Disorders

Answer 20

Enzyme defects
Defects in membrane receptors and transport systems
Alterations in structure, function or amount of non-enzyme proteins
Mutations resulting in unususal reactions to drugs

Question 21

chromosomal aberrations

Answer 21

duplication, inversion, deletion, insertion, translocation

Question 22

Major categories of congenital defects

Answer 22

1. Failure to develop completely
2. Failure of a part to close or coalesce
3. Defects of closure of abdominal wall
4. persistent vestigial or embryonic structures
5. Supernumerary organs and duplications
6. abnormal location: ectopic, aberrant
7. Improper mixture of tissues
8. Generalized defects
9. Cellular or enzymatic defects

Question 23

Major Causes of Congenital Defects

Answer 23

Genetic
Environmental – teratogens
Genetic + environmental (multifactorial)

Question 24

Environmental causes of Congenital Defects

Answer 24

Chemicals (Alcohol-fetal alcohol syndrome)
Drugs (Thalidomide)
Plants
Radiation
Teratogen: Infectious agents (Viruses: Feline parvovirus, Bovine viral diarrhea virus, Bluetongue virus)

Question 25

Principles for Teratogenesis

Answer 25

Genetic (species) susceptibility Stage of development at exposure Dose

Question 26

Immunodeficiency Syndromes

Answer 26

Immunodeficiency diseases occur when there is a failure of the immune system to protect the host from infectious organisms or the development of cancer.

Question 27

Two Types of Immunodeficiency Syndromes

Answer 27

primary: Congenital or genetic defect secondary: Acquired as a complication of: Infections Malnutrition Aging chemotherapy

Question 28

Primary Immunodeficiencies of Specific Immunity

Answer 28

SCID Agammaglobulinemia Selective IgM deficiency Selective IgA deficiency Thymic hypoplasia

Question 28

Primary Immunodeficiencies of Specific Immunity

Answer 28

SCID Agammaglobulinemia Selective IgM deficiency Selective IgA deficiency Thymic hypoplasia

Question 29

Severe Combined Immunodeficiency Syndrome (SCID)

Answer 29

Deficiencies in both humoral and cell-mediated immunity Multiple patterns of inheritance: Autosomal recessive, X-linked, Sporadic

Question 30

SCID in Horses

Answer 30

Autosomal recessive Arabian or Arabian crosses Severe lymphopenia (B and T) Develop agammaglobulinemia when colostral antibodies gone Die from various infections Equine adenovirus Pneumocystis Cryptosporidium ## Footnote Lymphoid hypoplasia Small thymus Lack of lymphoid follicles in tissues In spleen, lack of connective tissue stroma- differentiates from splenic lymphoid atrophy

Question 31

SCID in Foals: Genetic Defect

Answer 31

Mutation in gene encoding catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) Necessary for recombination of Ig heavy chain and TCR genes Cannot form functional V regions Also effective in DNA repair mechanisms

Question 32

SCID in Dogs

Answer 32

Basset Hounds X-linked Mutation in gamma subunit of IL-2, IL-4, IL-7, IL-19, IL-15 receptors Increased B lymphocytes, few to no T lymphocytes Thymus contains CD8+ >> CD4+ Block in T lymphocyte differentiation Hypogammaglobulinemia with normal IgM, decreased IgG and IgA Severe lymphoid hypoplasia

Question 33

X-linked SCID in Dogs: Mutation

Answer 33

Mutation in gamma subunit of IL-2, IL-4, IL-7, IL-19, IL-15 receptors 4-base pair deletion resulting in a stop codon Non functional T cells B cells cannot class switch Similar disease in Cardigan Welsh Corgis-insertion leading to stop codon

Question 34

Agammaglobulinemia in Horses

Answer 34

Absence of mature B lymphocytes and plasma cells No production of Ig TB, QH, Standardbred X-linked? not completely defined Extracellular bacterial infections of joints and respiratory system

Question 35

Selective Immune Deficiencies

Answer 35

IgM Foals Septicemia, pneumonia IgA G. Shep, Shar Pei, Irish Setter, Beagle Mucosal infections Normal numbers of IgA-type plasma cells Synthesis or secretion defect

Question 36

Thymic Hypoplasia

Answer 36

T lymphocyte deficiency Defective cell-mediated immune responses Nude mice important models of xenografts and allografts DiGeorge syndrome in humans Defect of development of 3rd and 4th pharyngeal pouches

Question 37

Primary Immunodeficiencies of Nonspecific Immunity | Brittany Spaniel

Answer 37

Complement system defects Brittany Spaniel Defect in C3 production Autosomal recessive Deletion mutation leading to stop codon Recurrent infections and membranoproliferative glomerulonephritis Clostridium pneumonia E. coli septicemia Klebsiella pyometra suppuratuve endometriosus | now talking about innate immune system

Question 38

Primary Immunodeficiencies of Nonspecific Immunity | Norwegian Yorkshire Pig

Answer 38

Dense Deposit Disease” Defect in Factor H of alternative complement pathway Factor H normally blocks formation of C3 convertase Lack in Factor H leads to unregulated production of C3b Membranoproliferative glomerulonephritis

Question 39

Primary Immunodeficiencies of Nonspecific Immunity: Chediak-Higashi Syndrome

Answer 39

Defective lysosomes, melanosomes, platelet dense granules, cytolytic granules Cats, cows, Aleutian mink, humans Wagyu cattle Hypopigmentation Bleeding tendencies (defective platelets) Ocular abnormalities (cataract) Recurrent infections (NQ defect) | might have plenty of neutrophils but they wont work.