Genetics of Birth Defects Flashcards
What 5 processes drive development on a cellular level?
- Gene regulation via transcription factors and epigenetic mechanisms
- Cell to cell signaling and morphogen
- Development of cell shape/polarity (cytoskeletal changes)
- Movement and migration of cells
- Programmed cell death (apoptosis)
How do transcription factors regulate genes during development?
Transcription factors can act as activators or repressors and their activity is transient
Transcription factor binding need to be re-establish after cell division - no memory
Examples: General transcription factors (CREBBP) and Specific Transcription factors (HOX)
In the case with the newborn with synpolydactly who has no other system abnormalities and family history shows positive hand abnormalities on mom and dad’s side, what does this show us?
Patient has mutation in the HOXD13 gene in the mother’s family and the HOXA13 gene in the father’s family.
The late HOX genes (11-13) are involved in development of distal pole of limbs and HOXA13 and HOXXD13 disturb development of fingers and toes.
Patient was double heterozygous so she showed more severe affect.
Also shows the limited impact of mutation in specific transcription factors since only limbs were affected.
What is an example of a mutation in general transcription factors?
Defect in general transcriptional coactivator CREBBP which causes Rubinstein-Taybi Syndrome
A rare autosomal dominant condition
Affects expression of many different genes and affects many different systems: CNS, eyes, heart, kidney
What is does signaling during development depend on?
Dependent on signaling through direct contact and by diffusible factors
What is an example of signaling through direct contact?
Juxtacrine signaling
Allows cells to interact with neighboring cells through cadherins or the notch pathway
Also allows cells to interact with extracellular matrix via integrin
What is an example of signaling via diffusible factors during development?
Paracrine/Autocrine signaling by diffusible morphogens
Morphogen binds to receptor in plasma membrane
Cells obtain position information from morphogen concentration
Morphogen binding triggers signaling cascades and activates transcription factors
How does paracrine signaling and morphogen concentration work together?
Paracrine signaling affects neighboring cells so mutations have local effects
Morphogens affect the development of cells over a long range which means different cell fates will be initiated based on morphogen concentration
A defect in morphogen secretion will have a negative impact over a long range - low morphogen secretion activity will alter cell fates
How does the Sonic Hedgehog (Shh) Morphogen signal?
Shh binds to the Patched receptor and releases inhibition on smoothened (SMO) protein so SMO is now activated
Signaling affects gene expression and stops cleavage of GLI protein (glioma-associated oncogenes)
Shh signaling also requires cholesterol
What would occur to Shh signaling if cholesterol synthesis was impaired? Provide an example.
Severe developmental phenotypes
Cholesterol synthesis defects cause autosomal recessive Smith Lemli Opitz syndrome
What is the effect of Shh?
Shh is secreted from the notochord and the floorplate of the neural tube and organizes brain and spinal cord cells
Shh also functions in limb development and is secreted from cells in polarizing region of limb bud (posterior)
What occurs if there are defects in Shh signaling?
Midline defects
What occurs when there is transplantation of Shh secreting cells to anterior region of a limb?
Duplication of posterior limb element since Shh is secreted from cells in polarizing region of limb bud (posterior)
What is an example of mutations in Shh gene?
Leads to autosomal dominant holoprosencephaly
Midline defects
What does Shh bind to and activate?
Shh binds to patched receptor and activates a large number of transcription factors
Released inhibition of SMO protein
How does retinoic acid, a morphogen, work?
Retinoic acid binds to retinoic acid receptors RAR/RAX and modulates HOX gene expression
Retinol (acne creams) is a teratogen
How does Wnt, a morphogen, function?
Wnt binds Frizzled receptors and increases cellular catenin levels (cancer)
What is an example of cells changing shape during development?
Renal tubules
Normal development - cells sense flow throw tubules and polarize by relocating erb-b2/EGFR and stop cell proliferation
In polycystic kidney disease: Cells still have erb-b2/EGFR exposed to the lumen since the cells can’t sense fluid flow. Leads to the cells continuing to grow and form cysts
What is an example of cell migration during development?
Development of CNS via LIS1 gene begins from the neural tube and neuronal stem cells divide and generate neuronal precursor cells.
The neuronal precursor cells migrate outward from the ventricle along a scaffold of glial cells
What occurs with a mutation in the LIS1 gene?
Interferes with migration of the neuronal precursor cells and causes lissencephaly (smooth brain)
What is the importance of apoptosis?
Necessary for
- development of the heart
- separation of individual digits
- perforation of the anal and choanal membranes
- establishment of a connection between uterus and vagina
- development of the immune system - eliminate cells that react to self
What are DSDs? What ones are more common?
Disorders in Sexual Development
Very rare forms - individuals with both testes and ovaries (ovotesticular DSD)
More frequent - Presence of testes or ovaries but external genitalia not matching gonads and/or presenting ambiguously
Sex determining region of Y (SRY) initiates male development, androgens from testes drive development of male genitalia
What does a 46, XX DSD produce?
No Y so ovaries will develop
No testes but androgen production still occurs
What does a 46, XY DSD produce?
Testes develop but no androgen production or response so no male external genitalia
What are the molecular causes of DSD?
Related to SRY/TDF region on the Y chromosome:
Y chromosome without functional SRY produces XY females (46, XY complete gonadal dysgenesis)
X chromosome with translocated SRY produces XX males (46, XX testicular DSD)
Enzymatic and receptor deficiencies:
Androgen insufficency leads to 46, XY DSD
Androgen synthesis without testes: 46, XX DSD
What is congenital adrenal hyperplasia?
Condition where adrenal glands produce precursors for androgen synthesis
Defect in cortisol and aldosterone production - can be life threatening and produce Addisonian shock. Most often caused by 21-hydroxylase deficiency
Intermediates shunted into androgen production instead of into making cortisol
Females develop high levels of androgens and develop ambiguous or male genitalia
What is androgen insensitivity?
46, XY DSD
Caused by deficient androgen production or poor androgen response
Possible causes:
Incomplete development of testes during embryogenesis
Often deficient steroid 5alpha-reductase
Androgen insensitivity syndrome - receptor or signaling defect
What is the importance of epigenetic programming? What can go wrong?
Epigenetic programming is necessary to achieve and maintain differentiation
Problems with epigenetic programming of cells can produce pools of incompletely differentiated cells
Incompletely differentiated cells might proliferate and become progenitor cells for tumors
