Development-Genetics Flashcards
Pierre Robin sequence
presentation
history of oligohydramnios
airway obstructions
cleft lip
small lower jaw
cleft lip a result of an original kidney dysfunction
extensive surgery
Treacher Collins Syndrome
mutation in treacle protein, auto dominant so high recurrence risk
present: small jaw, slanting palpebral fissures, malar hypoplasia, craniofacial abnormalities, airway obstruction
family hx of similar minor anomilies
regulative phase
early development
> end of week 2
can lose cells but compensated or embryo is aborted “all or nothing”
genome is maximally unmethylated aka open for epigenetic programming
primitve streak
emergence of primitive streak ends regulative phase aka no compensation after develops
becomes notochord
node @anterior end of streak
anterior/posterior axis
nodal gene
required for formation of primitive streak
nodal protein = morphogen (control over morphogenesis by concentration gradient)
-from TGF-beta family
dorsal/ventral development
induced by noggin and chordin morphogens from node
left/right formation
sonic hedgehog - morphogen, asymmetry of expression
cilia generate unidirectional current
defects occur rarely aka situs inversus
pattern formation
Hox genes- transcription factors,
tissue development depend on which set of hox genes is expressed aka hox code (bc each tissue express diff combos)
provide positional info
humans have 4 clusters arranged head to toe
epigenetic regulation
during development/differentiation
- developmental methylation: as cell lineages differentiate
- environment induced methylation: starvation or stress in 1st trimester
- parent of origin imprinting: only one active copy of a gene either from mom or dad (monoallelic expression)
Imprinting cycle
in gametogenesis: mark parent of origin chromo/imprint by de novo methylation
early gametogenesis: erase old poo imprint by erase methylation pattern
before implantation: erase old developmental pattern by erase methylation
x chromasome inactivation
all but one x chromos are inactivated but some can escape
mediated by transcription of XIST gene
DNA methylated + histones deacteylated
dysmorphology
aka developmental anomalies
describe birth defects by cause and mechanism
malformations
intrinsic abnormality in dev process
i.e polydactyly from error in HOX signalling
cause of defect
deformations
from extrinsic influence on dev
i.e. lack of amniotic fluid prevent extension of limbs/impairs dev
cause of defects
dysplasia
abnormal organization of cells w/i tissue
i.e hypochondroplasia from premature ossification of cartilage
cause of defect
disruption
extrinsic destroys developing tissue, started normally then killed off
i.e. amniotic bands wrap around limbs and cut off blood supply = amputate
cause of defect
syndromes
single defect simultaneously affects dev of diff systems
i.e down syndrome
mechanism
sequences
single defect that starts cascade of events
i.e Pierre Robin Sequence
mechanism
extent of damage
week 1-4 (blastogenesis): multiple major abnormalities in major organs/entire embryonic regions
week 5-8 (organogenesis): abnorms in specific organs, single major anomalies
week 9+ (post organ formation): mild effects
VACTERL association
group of birth defects for unknown reasons occur together, need 3+ for dx
V = vertebral
A= anal atresia
C= cardiac abnormalities
T= tracheo
E=esophagal fistual
R= renal
L=limb abnormalities
-assume blastogenesis phase
-maternal diabetes known risk factor
regulation of dev
36 cell divisions
one extra round likely fatal if early
segmental overgrowth if late
cellular processes driving development
- gene regulation (transcription factors and epigenetics)
- cell to cell signalling (morphogens)
- dev of cell shape/polarity (cytoskeletal changes)
- movement and migration of cells
- programmed cell death (apoptosis)
gene regulation in dev
transcription factors are transient
-general (CREBBP) or specific (HOX)
TF binding needs to be re-est after cell division bc no memory
CREBBP
general TF, also called CBP
defect causees Rubinstein-Taybi Syndrome
affects CNS, eyes, heart, kidney
cell to cell signalling
direct
direct contact: juxtacrine
-cell to cell = notch, cadherin
-cell to matrix = integrin
cell to cell signalling
indirect
or paracrine/autocine diffusible morphogens:
-bind to receptors in plasma mem
-cells obtain position info from morpho concentration
-morpho binding triggers signalling cascades and activates TFs
sonic hedgehog morphogen
binds Patched receptor > activates Smoothened protein = activiates large # TFs
-stops cleavage of GLI protein (glioma assoc oncogene)
requires cholesterol for signalling
patch binding activates large # TFs
Shh secretion and effect
1.organizes brain and spinal chord cells
-secreted from notochord and floorplate of neural tube = midline defects if Shh defect
- limb development
-secreted from cells in polarizing region of limb bud so transplantation to anterior region = duplication of posterior limb elements
Shh defects
midline and holoprosencephaly (forebrain not split into two halves)
mutations are autosomal dominant w/ variable expressivity
Smith Lemli Opitz syndrome= autosomal recessive from cholesterol syn defects impacts Shh signalling
Retinoic acid
binds retinoic acid receptors RAR/RAX
-modulates HOX expression
-retinol acne cream is a teratogen aka if during pregnancy then complications/defects
Wnt
binds Frizzled receptors
-inc cellular catenin levels (cancer)
polycystic kidney disease
normally: cells sense flow thru tubule and polarize by relocating erb-b2/ECFR from luminal to basal side
cells still have erb-b2/EGFR exposed to lumen (not relocated) so epithelial cells still respond to growth factors = cysts
LIS1 Mutations
interferes with migration of neuronal precursor cells outward = lissencephaly (smooth brain)
normally migrate from ventricle along scaffold of glial cells
apoptosis
necessary for
1. dev of heart
2. separation of digits
3. perforation of anal and choanal membranes
4. est of connnection b/t uterus and vagina
5. dev of immune system (eliminate cells that react to self)
disorders sexual development
DSD
ovotesticular DSD: indivs with both testes and ovaries, very rare
more freq: presence of both but external genitalia not match gonasds/present ambiguously
normal: SRY (sex determining region) initiates male dev, androgrens from testes drive dev of male genitalia
DSD molecular causes
SRY
Y chromo w/o functional SRY = XY female
X chromo with translocated SRY = XX males
DSD molecular causes
enzymes/receptors
androgen insufficiency w/testes = XY
androgen syn w/o testes = XX
congenital adrenal hyperplasia
defect in cortisol and aldosterone production from deficiency in sterioid 21-hydroxylase
-life threatening bc low BP and addisonian shock (stress response shock)
intermeds shunted into androgen production
46, XX DSD
masculinization of female babies (androgen syn w/o testes)
androgen insensitivity
46, XY, deficient androgen production or poor response but have testes
-incomplete dev of testes during embryogenesis
-deficient steroid 5alpha-reductase
androgen insensitivity syndrome
cancer
incompletely differntiated cells might proliferate and become progenitor cells for tumors
synpolydactyly
extra digits + fused
distal HOX genes so specific transcription factor defect
autosomal dominant so if parents then also child
