Genetics of Birth Defects

Question 1

What 5 processes drive development on a cellular level?

Answer 1

1. Gene regulation via transcription factors and epigenetic mechanisms
2. Cell to cell signaling and morphogen
3. Development of cell shape/polarity (cytoskeletal changes)
4. Movement and migration of cells
5. Programmed cell death (apoptosis)

Question 2

How do transcription factors regulate genes during development?

Answer 2

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)

Question 3

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?

Answer 3

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.

Question 4

What is an example of a mutation in general transcription factors?

Answer 4

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

Question 5

What is does signaling during development depend on?

Answer 5

Dependent on signaling through direct contact and by diffusible factors

Question 6

What is an example of signaling through direct contact?

Answer 6

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

Question 7

What is an example of signaling via diffusible factors during development?

Answer 7

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

Question 8

How does paracrine signaling and morphogen concentration work together?

Answer 8

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

Question 9

How does the Sonic Hedgehog (Shh) Morphogen signal?

Answer 9

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

Question 10

What would occur to Shh signaling if cholesterol synthesis was impaired? Provide an example.

Answer 10

Severe developmental phenotypes

Cholesterol synthesis defects cause autosomal recessive Smith Lemli Opitz syndrome

Question 11

What is the effect of Shh?

Answer 11

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)

Question 12

What occurs if there are defects in Shh signaling?

Answer 12

Midline defects

Question 13

What occurs when there is transplantation of Shh secreting cells to anterior region of a limb?

Answer 13

Duplication of posterior limb element since Shh is secreted from cells in polarizing region of limb bud (posterior)

Question 14

What is an example of mutations in Shh gene?

Answer 14

Leads to autosomal dominant holoprosencephaly

Midline defects

Question 15

What does Shh bind to and activate?

Answer 15

Shh binds to patched receptor and activates a large number of transcription factors

Released inhibition of SMO protein

Question 16

How does retinoic acid, a morphogen, work?

Answer 16

Retinoic acid binds to retinoic acid receptors RAR/RAX and modulates HOX gene expression

Retinol (acne creams) is a teratogen

Question 17

How does Wnt, a morphogen, function?

Answer 17

Wnt binds Frizzled receptors and increases cellular catenin levels (cancer)

Question 18

What is an example of cells changing shape during development?

Answer 18

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

Question 19

What is an example of cell migration during development?

Answer 19

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

Question 20

What occurs with a mutation in the LIS1 gene?

Answer 20

Interferes with migration of the neuronal precursor cells and causes lissencephaly (smooth brain)

Question 21

What is the importance of apoptosis?

Answer 21

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

Question 22

What are DSDs? What ones are more common?

Answer 22

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

Question 23

What does a 46, XX DSD produce?

Answer 23

No Y so ovaries will develop

No testes but androgen production still occurs

Question 24

What does a 46, XY DSD produce?

Answer 24

Testes develop but no androgen production or response so no male external genitalia

Question 25

What are the molecular causes of DSD?

Answer 25

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

Question 26

What is congenital adrenal hyperplasia?

Answer 26

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

Question 27

What is androgen insensitivity?

Answer 27

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

Question 28

What is the importance of epigenetic programming? What can go wrong?

Answer 28

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