Development-Genetics Flashcards by Haley T

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

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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

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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

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primitve streak

emergence of primitive streak ends regulative phase aka no compensation after develops

becomes notochord

node @anterior end of streak

anterior/posterior axis

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nodal gene

required for formation of primitive streak

nodal protein = morphogen (control over morphogenesis by concentration gradient)
-from TGF-beta family

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dorsal/ventral development

induced by noggin and chordin morphogens from node

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left/right formation

sonic hedgehog - morphogen, asymmetry of expression

cilia generate unidirectional current

defects occur rarely aka situs inversus

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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

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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)

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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

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x chromasome inactivation

all but one x chromos are inactivated but some can escape

mediated by transcription of XIST gene

DNA methylated + histones deacteylated

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dysmorphology

aka developmental anomalies

describe birth defects by cause and mechanism

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malformations

intrinsic abnormality in dev process

i.e polydactyly from error in HOX signalling

cause of defect

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deformations

from extrinsic influence on dev

i.e. lack of amniotic fluid prevent extension of limbs/impairs dev

cause of defects

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dysplasia

abnormal organization of cells w/i tissue

i.e hypochondroplasia from premature ossification of cartilage

cause of defect

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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

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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 2. 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