Developmental abnormalities mechanism

Question 1

How are developmental diseases manifested?

Answer 1

• Congenital (Birth)
  
  • abnormal embryogenesis
• Acquired (after Birth)
  
  • abnormal postnatal development
  • often genetically caused

Question 2

What are the Genetic Factors that cause developmental disease?

Answer 2

• 3 major categories:
  
  • Chromosomal abnormalities
  • Single gene abnormalities
  • Multifactor abnormalities

Question 3

What are the Chromosomal abnormalities?

Answer 3

• Most common abnormality associated with severe morphological defects
• Abnormalities mainly due to changes in chromosome number or structure
• Most of these defects result in embryonic death, abortion or stillbirth

Question 4

What are the changes seen in Chromosome number?

Answer 4

• Monosomy - 1 less chromosome
• Trisomy - 1 extra chromosome

Question 5

What is Mosaicism?

Answer 5

Some chromosomal aberrations can be transmitted through some, but not all cell lines during embryonic development

Question 6

What are the changes in chromosome structures?

Answer 6

• Chromosome breakage can result in loss or rearrangement of chromosomes
• Chromosomes can be deleted, inverted or translocated

Question 7

What are single gene abnormalities?

Answer 7

• Result in changes in a single protein
  
  • May be structurally altered or expression may be affected
• Often manifested as a functional abnormality
• NOT commonly associated with severe morphological defects

Question 8

What categories of genes are affected by single gene abnormalities?

Answer 8

• Structural proteins
  
  • collagen dysplasia
• Receptor Proteins
  
  • Bovine leukocyte adhesion deficiency syndrome
• Enzymes
  
  • Lysosomal storage disease
• Regulatory proteins
  
  • Alteration of metabolic pathways

Question 9

How are abnormal genes get inherited?

Answer 9

• Autosomal
  
  • Dominant: appear in every generation, onset in later life
  • Recessive: May not appear in every generation, onset in early life
• Sex-linked
  
  • Mainly x-linked recessive
    
    • Asymptomatic females to some males

Question 10

What are multifactorial genetic abnormalities?

Answer 10

• Diseases due to 2 or more gene abnormalities usually along with some environmental factors
• Common with many normal traits, as well as both developmental and non-developmental disease

Question 11

What is Syndactyly?

Answer 11

• Condition in cattle
• Characterized by fusion or non-division of the 2 functional digits
  
  • “Mulefoot”
• Autosomal recessive trait with incomplete (79% in holsteins) penetrance
• One of the most common deformities of the hands and feet in humans
  
  • “Joined finger”
  • 3 in 10,000 persons

Question 12

What breeds have been affected by Bovine Syndactyly?

Answer 12

• Holstein
• Angus
• Simmental
• Brown Swiss
• Chianina
• Japanese Native
• Hariana
• Swedish Red Pied
• Czech Black Pied

Question 13

What affect does Syndactyly genes have on milk production?

Answer 13

• In 1970s
• Discovered that carriers of syndactyly locus (SY+/sy) had superior milk and butterfat production compared to non-carriers (SY+/SY+)

Question 14

Where does the defect for Syndactyly occur?

Answer 14

• Mapped to bovine Chromosome 15 in 1996
  
  • Completed with pedigree analysis and genotyping
• Mapped to a 3.5mb critical interval of the chromosome in 2006
• Due to mutation in the LRP4 gene
  
  • 2 base-pair substitution in exon 33
    
    • Glycine replaced cysteine
  • Mutation affects 2 amino acids, probably alters disulfide bond production

Question 15

What is the LRP4 gene?

Answer 15

• Member of the LDL receptor family
• Has multiple EGF-like domains which play a role in a variety of extracellular events
• Signaling pathways are not fully described, but it is negative regulator of the Wnt-B-catenin signaling pathway
  
  • Wnt is a pathway mainly involved in embryogenesis and tumorigenesis
  • B-catenin interacts with various transcription factors to activate wnt target genes

Question 16

What are the Environmental factors that lead to developmental abnormalities?

Answer 16

• Includes any external factor that can affect embryogenesis
• Ex:
  
  • Infection
  • Chemical (Toxins)
  • Nutrition

Question 17

How does Infection cause developmental abnormalities?

Answer 17

• Fetal infection by a wide variety of agent can cause developmental anomalies
• The age of fetal exposure has a critical impact on the nature of the defect
• Ex:
  
  • Bovine diarrhea virus
  • Feline panleukopenia virus
  • Bluetongue virus (cattle and sheep)

Question 18

How does Bovine virus diarrhea virus (BVDV) affect fetuses?

Answer 18

• Exposure before 100 days:
  
  • Fetal death
• Exposure at 100-170 days:
  
  • Various anomalies including cerebellar, cerebral and ocular lesions
• Exposure after 170 days:
  
  • Persistent infection and lymphoid atrophy

Question 19

How does Bluetongue virus affect sheep?

Answer 19

• If viral exposure during development of cerebral hemispheres damages developing neurons and results in ventricular/cerebral anomalies (hydranencephaly)
• Exposure at 50-55 days gestation:
  
  • Hydranencephaly (see picture)
• Exposure at 75 days gestation:
  
  • Porencephaly

Question 20

What role do chemicals play in developmental abnormalities?

Answer 20

• Maternal exposure to many different chemical can cause fetal anomalies
• These are most common in grazing animals exposed to toxic plants
• Pharmacological agents and industrial chemical can induce anomalies
• The nature of the defect is highly dependent on the time of exposure during gestation

Question 21

How does Veratrum californicum exposure effect sheep?

Answer 21

• Ingestion at 14 days gestation:
  
  • Cyclopia and severe craniofacial defects (see picture)
• Ingestion at 29 days of gestation:
  
  • Metacarpal and metatarsal shortening
• Ingestion at 31 days of gestation:
  
  • Tracheal and laryngeal stenosis

Question 22

How does Veratrum californium lead to cyclopia?

Answer 22

• Cholesterol-like alkaloids in Veratrum can bind Shh, but don’t activate it
  
  • Inactive Shh and lack of many of the critical steps in cell differentiation that are necessary for normal embryogenesis
• May inhibit other activities of cholesterol as well

Question 23

What is cyclopia in sheep?

Answer 23

• A Severe manifestation of Holoprosencephaly (HPE)
  
  • resulting from failure of the embryonic forebrain to subdivide properly
  • Morphology can range from a single upper incisor, to cyclopia and other severe anomalies
  • Causes include a wide variety of genetic and environmental agents
    
    • Veratrum californicum

Question 24

What are the functions of cholesterol?

Answer 24

• Structural component of cell membranes
• Ratio of cholesterol to membrane phospholipids affects the stability, permeability and protein mobility of the membrane
  
  • High ratios = high stability and low permeability
  • Low ratios = highly fluid and permeable
• Precursor of steroid hormones
• Precursor of bile acids

Question 25

What is the Sonic Hedgehog gene (Shh)?

Answer 25

• Shh protein is important for normal nervous system development
• Its a transcriptional regulatory protein
• Acts as a morphogen;
  
  • a molecule that diffuses to form a concentration gradient which influences the type of cell that will develop
• Shh signaling pathways regulate organogenesis
  
  • influences development of nervous tissue, limbs, hair, gut, and pancreas
• Regulates stem cell division in adults
  
  • implicated in development of some types of neoplasia

Question 26

What happens when Shh protein is activated?

Answer 26

1. Shh is secreted as a preprotein
2. It undergoes cholesterol-mediated cleavage to become activated prior to secretion
3. Shh binds to patched (ptc) to allow smoothened (smo) to function
   
   1. Ptc is a membrane protein inhibitor of smo
   2. When bound to Shh it also has a cholesterol sensing function, to measure and regulate the amount of cholesterol in a cell
   3. Smo is a signal transducer that enhances entry of proteins into the nucleus which activate transcription

Question 27

What happens when Shh proteins is present?

Answer 27

• When Shh binds ptc, it relieves the inhibition of smo, smo allows transcription to occur
• There is also normal cholesterol trafficking and cell differentiation

Question 28

What happens when Shh is absent?

Answer 28

• When Shh is absent, ptc inhibits smo and activates a transcriptional repressor that inhibits transcription
• Absence of Shh results in abnormal cholesterol trafficking and abnormal cell differentiation

Question 29

How does nutrition lead to developmental abnormalities?

Answer 29

• Failure of access to proper nutrients can affect fetal development
• Uterine or placental abnormalities can affect nutrient transfer
• Nutritional deficiencies or toxicity can alter fetal development

Question 30

How does Vit A deficiency cause developmental abnormalities?

Answer 30

• Results in interference with normal bone formation to cause anomalies including
  
  • Microphthalmia
  • Polydactyly
  • Arthrogryposis
  • Cleft palate
  • Thickening of bones of the skull