Genetics of Birth Defects

Question 1

5 processes that drive development on cellular level

Answer 1

• -gene regulation
• -cell-cell signaling
• -development of cell shape and polarity
• -movement and migration of cells
• -programmed cell death

Question 2

Two Types of Transcription Factors

Answer 2

• -General- defects in GTF’s will affect expression of many genes (ex. CREBP defects = Rubenstein-Taybi Syndrome)
• -Specific-only function in specific cells at specific times

Question 3

Since Transcription factor regulation is not super stable what process helps regulation?

Answer 3

–epigenetic changes and processes

Question 4

Impaired morphogen gradient

Answer 4

• -will causes cells to have different developmental fates than what they are tended to be
• • even heterozygous mutations will affect gradient of morphogens because there will be less morphogen production

Question 5

Mutation in Shh signaling and its gradient?

Answer 5

–causes midline (holoprosencephaly) defects: failure to develop midface and the forebrain

Question 6

Shh Morphogen

Answer 6

• -secreted from notochord and floorplate of neural tube
• -Shh gradient helps organzing the different cells in brain and spinal cord
• -must be cholesterylated (cholesterol synthesis problems have severe developmental phenotypes)

Question 7

Changes in cell shape and organization

Answer 7

• -cells respond to environmental clues by changing shape and polarity
• -rearrange cytoskeleton and polarizing the secretion of proteins to the apical or basal surface of cell

Question 8

Polycystic Kidney Disease

Answer 8

• -normally, kidney epithelial cells need to sense flow of fluid to develop correct polarity and shape
• -fluid flow stops cell proliferation
• -mutated genes polycystin 1/2 lead to cells not being able to sense fluid stream so they continuously divide leading to cysts

Question 9

Cell Migration and Problems w/ it

Answer 9

• -CNS cells migrate during develop
• -precursor cells migrate in waves out from ventricle
• -mutation in LS1 gene (Lissencephaly) can interfere w/ migration pattern (smooth brain, mental retardation)

Question 10

Cellular Apoptosis during Development and What it is important for?

Answer 10

• -some cells need to undergo programmed cell death during development
• -important for development of heart, separation of individual digits
• -perforation of anal and choanal membranes
• -establishment of connection between vagina and uterus
• -development of immune system
• -ex. certain lymphocyte cells need to undergo apoptosis, if they dont it can lead to autoimmune diseases

Question 11

Genetic sex of embryo is determined by?

Answer 11

presence or absence of Y chromo

• –critical region on Y chromo is SRY (sex-determining region of Y chromo)
• -SRY region contains TDF (testes determining factor)

Question 12

Hermaphroditism vs Pseudohermaphroditism

Answer 12

• -hermaphro: when Pt. has both ovaries and testicular tissue
• -Pseudo: either have testes OR ovarian tissue but the Pts. phenotype does not represent thier genetic sex

Question 13

Deletion of SRY region

Answer 13

–embryo develops female w/ XY chromos

Question 14

Translocation of SRY region

Answer 14

–to X chromo so XX karyotype gives a male

Question 15

Female Pseudohemaphroditism

Answer 15

• -normal ovaries but ambiguous or male genitalia
• -congenital adrenal hyperplasia is cause
• -defect in 21-hydroxylase so cortisol cant be made so its shunted other pathway to be made into androgens
• -high levels of androgens = development of male genitalia

Question 16

Male Pseudohermaphroditism (3 possible causes)

Answer 16

• -failure to develop unambiguously male genitalia results from:
• -defect in testes development during embryogenesis
• -problem in androgen synthesis
• -deficiency of androgen receptor production or signaling by target cells

Question 17

Development and Cancer (tumor progenitor cells)

Answer 17

• -epigenetic processes are crucial for cellular development
• -DO NOT want cells going in reverse after being developed: epigenetic changes make sure they dont
• -abnormalities of epigenetic processes of stem cells generate pool of incompletely differntiated cells which retain some embryonal potential = benign tumor
• -from here oncogenes and tumor supressor genes can mutate leading to malignant tumor formation = cancer

Question 18

Gatekeeper Mutation

Answer 18

–mutation in tumor suppressor genes or oncogenes

Question 19

Tumor Progenitor Cell Model

Answer 19

• -arise during development due to epigenetic changes
• -followed by gatekeeper mutation to suppressor genes or oncogenes to give benign tumors
• -epigenetic and genetic plasticisty help evolve benign growth to malignant