Developmental abnormalities mechanism Flashcards
1
Q
How are developmental diseases manifested?
A
- Congenital (Birth)
- abnormal embryogenesis
- Acquired (after Birth)
- abnormal postnatal development
- often genetically caused
2
Q
What are the Genetic Factors that cause developmental disease?
A
- 3 major categories:
- Chromosomal abnormalities
- Single gene abnormalities
- Multifactor abnormalities
3
Q
What are the Chromosomal abnormalities?
A
- 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
4
Q
What are the changes seen in Chromosome number?
A
- Monosomy - 1 less chromosome
- Trisomy - 1 extra chromosome
5
Q
What is Mosaicism?
A
Some chromosomal aberrations can be transmitted through some, but not all cell lines during embryonic development
6
Q
What are the changes in chromosome structures?
A
- Chromosome breakage can result in loss or rearrangement of chromosomes
- Chromosomes can be deleted, inverted or translocated
7
Q
What are single gene abnormalities?
A
- 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
8
Q
What categories of genes are affected by single gene abnormalities?
A
-
Structural proteins
- collagen dysplasia
-
Receptor Proteins
- Bovine leukocyte adhesion deficiency syndrome
-
Enzymes
- Lysosomal storage disease
-
Regulatory proteins
- Alteration of metabolic pathways
9
Q
How are abnormal genes get inherited?
A
-
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
- Mainly x-linked recessive
10
Q
What are multifactorial genetic abnormalities?
A
- 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
11
Q
What is Syndactyly?
A
- 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
12
Q
What breeds have been affected by Bovine Syndactyly?
A
- Holstein
- Angus
- Simmental
- Brown Swiss
- Chianina
- Japanese Native
- Hariana
- Swedish Red Pied
- Czech Black Pied
13
Q
What affect does Syndactyly genes have on milk production?
A
- In 1970s
- Discovered that carriers of syndactyly locus (SY+/sy) had superior milk and butterfat production compared to non-carriers (SY+/SY+)
14
Q
Where does the defect for Syndactyly occur?
A
- 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
- 2 base-pair substitution in exon 33
15
Q
What is the LRP4 gene?
A
- 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
18
Q
How does Bovine virus diarrhea virus (BVDV) affect fetuses?
A
- 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
19
Q
How does Bluetongue virus affect sheep?
A
- 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
21
Q
How does Veratrum californicum exposure effect sheep?
A
- 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
24
Q
What are the functions of cholesterol?
A
- 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
26
Q
What happens when Shh protein is activated?
A
- Shh is secreted as a preprotein
- It undergoes cholesterol-mediated cleavage to become activated prior to secretion
-
Shh binds to patched (ptc) to allow smoothened (smo) to function
- Ptc is a membrane protein inhibitor of smo
- When bound to Shh it also has a cholesterol sensing function, to measure and regulate the amount of cholesterol in a cell
- Smo is a signal transducer that enhances entry of proteins into the nucleus which activate transcription
30
Q
How does Vit A deficiency cause developmental abnormalities?
A
- Results in interference with normal bone formation to cause anomalies including
- Microphthalmia
- Polydactyly
- Arthrogryposis
- Cleft palate
- Thickening of bones of the skull
