Developmental genetics: Exam 2

Rearrangement of the single layer into trilaminar structure

Ectoderm, mesoderm, endoderm

gastrulation

key role of hox genes

positioning of cells and tissues, craniofacial development and limb formation

3 layers formed by gastrulation from what and when

ectoderm, endoderm, mesoderm

blastula

14 to 28 days gestation

folding process turns the neural plate into the neural tube

closure occurs at 5 different sites

separation of the ectoderm into neural tube, epidermis, neural crest cells

neurulation

mesoderm components

notochord

dorsal mesoderm

intermediate mesoderm

lateral mesoderm

head mesenchyme

induces neural tube and body axis

notochord

axial skeleton, skeletal muscle, and CT

dorsal mesoderm

kidneys and GU

intermediate mesoderm

heart, viscera, body wall

lateral mesoderm

eye and head muscles

head mesenchyme

when are many genes activated

mesoderm (likely culprits as birth defect causes)

formation of the primitive streak creates what axis

posterior anterior axis

in which neural development stage does formation of the primitive streak occur

during gastrulation

when does forming of the:

digestive tract

lining of the respiratory tree

lining of middle ear, thymus, parathyroids, and thyroid occur

during endoderm

_______ genes key for positioning of cells and tissues

- Mutations cause abnormalities of limb formation

hox

situs solitus

normal arrangement of organs

situs inversus

reversed position of organs

(mirror image of situs solitus)

situs ambiguus

randomization of organ placement

(heterotaxy)

what abnormalities of asymmetry causes big effects to especially affects heart and spleen?

situs ambiguous

the turning on and off by different _____ genes making us very different by:

- directs fx and movement of cells

- limb movement

- skull structure development

i) muscles and bones of head and neck

hox

Prevalence of limb defects second only to _______ defects

- Complex formation

- Involvement of multiple axes

Limb derived primarily from ______________

- Somitic and lateral plate

Induction of fore- and hind-limbs first step

heart, mesoderm

A_________ ectodermal ridge influences distal progression of limb development

- Stimulates proliferation of mesodermal cells

Zone of p___________- activity specifies anterior/posterior information

- Key for t________-f________ differentiation

apical, polarizing, thumb, finger

what condition is this?

Malformation of the radial, thenar, and/or carpal bones

- Often more severe in left than right

- Can have sloping shoulders and restricted movement at the joint

Congenital heart disease in 75% of individuals

- Most commonly ASDs and VSDs

Cardiac conduction disease

- Can progress to complete heart block with or without atrial fibrillation

- T-box transcription factor

thumb becomes more "—————", looks more like a finger than a thumb

mutation?

Holt-Oram Syndrome

digitized

TBX5 mutation

organogenesis happens once this occurs

once the axes are established

organogenesis

like w like

cells w common fx become tissues

pattern recognition

organogenesis

____________ exchange between tissues promote growth and differentiation

Signal

mutations in this gene cause cleidocranial dysostosis:

Open fontanelle

Hypertelorism (wide spaced eyes)

Absent clavicles

RUNX2

what is RUNX2 and what does it regulate

transcription factor

regulates skeletal formation (skeletal formation dependent upon osteoblasts)

term for wide spaced eyes

Hypertelorism

alterations in this gene cause aniridia

PAX6

term for absence of an iris

aniridia

(very light sensitive)

can manipulate the gene to express in a different location

ectopic expression

this normal heart is called what

patent ductus arteriosus

what category of defects is this

defects occur due to intrinsically abnormal development (3-5% common)

- but few have multiple malformations

a. genetic (chromosomes, genes)

b. teratogens (exposures)

c. fetal environment (high fever, blood sugars being off)

malformations

this malformation is characterized by thrombocytopenia and absent radius

but still have thumb

TAR syndrome

have radi but no thumbs

Fanconi anemia

Deformation due to extrinsically abnormal development

example: ____________ (metatarsus adductus)

defect to (nondisruptive/disruptive)? mechanical force, resulting in abnormal form of position

usually NOT genetic

good prognosis

example: __________________

Deformation

clubfeet

nondisruptive

plagiocephaly

skull has different bones, open sutures in b/w and eventually fuse, if do not have good muscle tone may be laying on side and will have flattening on one side and start making it worse on the flat side "misshapen head size and shape"

plagiocephaly

(can correct w helmets)

an example of defect due to non-disruptive mechanical force (deformation)

deformation is different than disruption b/e w disruption there is lasting effects since tissue can not _______ back

grow

example of disruption

amniotic bands

disruption is defect due to disruptive _______________ force

not genetic

lasting effects

mechanical

malformation, deformation, disruption, dysplasia

gestational issues

_______________

Anomalous organization of cells or tissues

Localized vs. generalized:

Localized

- Severity depends on extent of involvement

Genetic at cellular level

Generalized

- Usually genetic, and heritable with variable expressivity

Examples:

Skeletal dysplasias

Dysplasia

_______________ signaling families

- fibroblast growth factors

secretion into surrounding spaces to influence fx (you be liver etc)

paracrine

What type of conditions are described by this?

Collectively 1:5000 birth

Variety of inheritance patterns

- Most common are autosomal dominant

i) Often _______ mutations

Many are perinatal _________

- Also have less severe forms that can look similar

Detection in utero in many cases

- High resolution ultrasound techniques

- shortened femur etc

skeletal dysplasias

new

lethal

Naming of skeletal dyspasias by what pt of body is affected (dysplasia localized) PT 1

_____________ = spine

______________ = ossification separated from shaft by epiphyseal cartilage

________________ = growth area between epiphyses and diaphyses

_______________= shaft

Spondylo

Epiphyseal

Metaphyseal

Diaphyseal

Naming of skeletal dyspasias by what pt of body is affected (dysplasia localized) PT 2

(shortened)

__________________: humerus, femur

__________________: radius/ulna, tibia/fibula

__________________: hand, foot

__________________: entire limb

rhizomelic

mesomelic

acromelic

micromelic

what is this condition? :

- Long trunk and very short curved limbs

- Flat ossification centers of the vertebral bodies

- Femora and other bones are very short and usually curved (SMALL RIBCAGE !! = DEATH, lungs restrictive growth)

Thanatophoric dysplasia (type of skeletal dysplasia)

(small ribcage so too constrictive for lungs)

term for death dealing

thanatophoric

What is this condition? :

Classic dwarfism- rhizomelic shortening of long bones

1/20,000

80% _____ mutation (advanced ________________ AGE 45 or older)

- Most mutable position in genome

"Trident hand shape"

Bowing because of bone length discrepancy

Achondroplasia

new, paternal

what condition does this person have:

trident hand

hip bones changes

additional skin gold

achondroplasia

advanced paternal age

45 yo

babies w achrondraplasia can get up ___________ hands

without

Achondroplasia

- __________ intelligence

- _________ delays (hypotonia, l_________ head)

- adult height = ____ inches

complications: (due to small features)

Otitis media (midface hypoplasia)

Respiratory problems and apnea

Foramen magnum compression

Midface hypoplasia

Hydrocephalus

normal

motor, large

50

what is this disability?

Similar features to achondroplasia but less pronounced

Often diagnosed at a later age

Height can range from 50-65 inches but usually around __ feet

Increased incidence learning problems and intellectual disability

Hypochondroplasia, 5

ALL3 CONDITIONS DUE TO MUTATIONS IN FGFR3 gene

disease dependent upon mutation location within the gene (protein has interactions w at least 22 different FGFs)

Hypochondroplasia, Thanatophoric dysplasia, Achondroplasia

What condition is this?

- Premature closure of the cranial sutures (abnormal growth occurs in the opposite of where the suture closes)

i) prominent eyes

- Syndromes have characteristic involvement of certain sutures

- Can also have limb involvement as well

- Mutations in FGFR1, FGFR2, FGFR3, TWIST

- often need surgical correction to allow for brain growth

Craniosynostoses

abnormal growth occurs in the _____________ direction of where the suture closes

opposite

Paracrine signaling families

Fibroblast Growth Factors (FGFs)

Hedgehog

Wingless (Wnt)

Transforming Growth Factor β (TGFBs)

(this signaling molecule) was first named from association with Drosophila

which binds to PTCH protein and (does this action) on PTCH

Active PTCH inhibits SMO signaling pathway

i) Active SHH --> active SMO pathway

Key in _______ formation

signaling to things outside of cell to what is supposed to occur inside of cell

sonic hedgehog (SHH)

inactivates

axis (neural tube)

What condition is this? (Sonic Hedgehog)

Mutations in SHH

- Other genes/ syndromes can also cause phenotype

High variability of presentation

- Cyclopia

- Central maxillary incisor

- Anywhere in between

Holoprosencephaly

(brain does not split correctly)

mutation in SHH

Holoprosencephaly

What condition is this? (Sonic Hedgehog)

Abnormality in cholesterol metabolism

i) Deficiency in 7-dehydrocholesterol (7DHC) reductase

Small head and body size

Intellectual disability

Ambiguous genitalia (cholesterol pathway overlaps w TST pathway (produce too much sex hormones)

Y-shaped 2/3 toe syndactyly

Varied clinical phenotype

Smith-Lemli-Opitz Syndrome

What condition is this? (Sonic Hedgehog)

AKA more appropriate: Nevoid basal cell carcinoma syndrome

Multiple basal cell carcinomas

Macrocephaly

Jaw keratocysts

Mutations in the PTCH gene

- Somatic PTCH mutations also a component of some cancers

Gorlin Syndrome

mutations in PTCH gene

Gorlin Syndrome

dimple in hand, soak in water as you dry you see pits

Gorlin Syndrome

What condition is this? (Sonic Hedgehog)

Preaxial polydactyly

Macrocephaly

Seizures, hydrocephalus, and intellectual disability in severe cases

Caused by mutations in GLI3

extra digits and webbing of digits (on pre axial side)

Greig Cephalopolysyndactyly Syndrome

mutations in GL13

Greig Cephalopolysyndactyly Syndrome

What condition is this? (Sonic Hedgehog)

Broad and angulated thumbs and big toes

Postnatal small head and body size

Mod-severe intellectual disability

Most have mutations in CREBBP

thumbs = angulated and broad

Rubinstein-Taybi Syndrome

mutations in CREBBP

Rubinstein-Taybi Syndrome

Responsible for dorsal/ventral axis

Key in formation of the brain, muscle, gonads, and kidneys

Seen in disorders of limb structure and gonadal development

Paracrine signaling families

Wingless (Wnt)

Paracrine signaling families

What type of growth factor?

- Many genes fall within this subtype

- Largely associated with bone formation

- Present in hetero- and homodimers

Transforming Growth Factor β (TGFBs)

___________ signaling families

Fibroblast Growth Factors (FGFs)

Hedgehog

Wingless (Wnt)

Transforming Growth Factor β (TGFBs)

Paracrine

RAS-opathies

___________ syndrome:

Common genetic form of short stature

5’5” males 5’ females

Congenital heart defects

Pulmonic stenosis most common

Cardiomyopathy later

Undescended testes

Minor learning difficulties

PTPN11 mutations

Noonan

this signaling pathway is common for signaling inside the cell (name of signaling pathway)

RAS-MAPK signaling pathway. group of conditions are called RAS-opathies

PTPN11 mutations

Noonan Syndrome

+

LEOPARD Syndrome (also RAF1 and BRAF )

RAS-opathies

Lentigines

ECG abnormalities

Ocular hypertelorism

Pulmonic stenosis

Abnormal genitalia

Retardation of growth

Deafness, sensorineural

Common mutations in PTPN11, also RAF1 and BRAF

LEOPARD syndrome

(lentigines)

terms for freckles

lentigines

RAS-opathies

Pulmonic stenosis or other CHD

- Cardiomyopathy too

Sparse, curly hair

Sparse or absent eyebrows

Mild-severe intellectual disability

Risk for neoplasia

- Acute lymphoblastic leukemia

Mutations often in BRAF

MAP2K1, MAP2K2, KRAS too

Cardiofaciocutaneous syndrome

Mutations often in BRAF

MAP2K1, MAP2K2, KRAS too

Cardiofaciocutaneous syndrome

RAS-opathies

Severe postnatal feeding difficulties

Short stature

Intellectual disability

Curly, sparse fine hair

Congenital heart disease and cardiomyopathy

15% lifetime risk for malignancy

HRAS mutations

Costello syndrome

HRAS mutations

Costello Syndrome

RAS-opathies

Café-au-lait (coffee with cream) spots

Benign nerve tumors called neurofibromas

Freckling in the inguinal (groin) or axillary (armpit) regions (freckles= sunlight, so if not in sunlight areas, a clue)

Eye changes

Learning problems or intellectual disability

Progressive disorder

- Symptoms can get worse over time

MOST PPL HAVE VERY MILD SYMPTOMS (high variability even w/in families)

Neurofibromatosis type 1

Mutations in ___ gene:

- Tumor suppressor gene - regulating growth

- Autosomal dominant condition

- ~50% are due to a new mutation

Neurofibromatosis type 1

Neurofibromatosis type 1 is COMPLETELY different condition than neurofibromatosis type 2

- Poorly-named condition not at all related to NF1

- 10x rarer than NF1

- Has been renamed to:

schwannomatosis

For proper embryonic and fetal development ________-dimensional axes must be established

Numerous genes are responsible for ____________ at critical times in development

Interrupted, incorrect, or incomplete signaling can lead to localized (birth defects) or systemic (syndromic) _______________________s

three

signaling

abnormalities

What condition is this?

Caused by FBN1 mutations

Tall, thin body habitus

Disportionately long limbs (fingers are longer, chest is thinner)

Increased risk for retinal detachment

Significant risk for aortic root dilation and/or dissection

- Previously ineffectively treated with beta blockers

- Treatment with Losartan shows some promise but not perfect

Marfan syndrome

(as states, risk of aortic root dissection + retinal detachment so docs will refer often to genetics to see

thumb sign, thumb sticks out, pinky and thumb wrap around wrist, will overlap)

FBN1 mutations

Marfan syndrome

you need both copies of the gene to be non functional to be expressive

Genotypically dominant

But

Phenotypically recessive (second copy needs to mutate for symptoms)

this describes this hypothesis…

Knudson's Two-Hit Hypothesis

when a phenotype is 100% penetrant the mutation is always

symptomatic

Encourages growth (gas pedal)

Only one needed to be altered (turned on MORE) to throw off balance

proto-oncogenes

the brakes - both copies need to "give out"

Tumor suppressors

a phenotype is 60% penetrant is the idea of

incomplete penetrance

refers to the range of signs and symptoms that can occur in different people with the same genetic condition.

for example, the features of Marfan syndrome vary widely— some people have only mild symptoms (such as being tall and thin with long, slender fingers), while others also experience life-threatening complications involving the heart and blood vessels. Although the features are highly variable, most people with this disorder have a variant in the same gene (FBN1).

Variable expressivity

Quantitative measurement

likelihood of any symptoms with mutation (light switch on/off)

Penetrance

What is this showing?

Regulation of when and how much a gene is transcribed

- Especially key in developing embryo

One transcription factor often regulates multiple genes

- Signaling cascade

Mutation in one transcription factor could have global effect

- (MeCP2 in Rett syndrome)

Transcription factors

(inside the cell signaling, regulate genes, hit promoter to say "gene turn on" at key times in development - this is the regulation part)

What is this showing?

Scaffolding for tissues and organs

- Transient adherence to cell surface via integrins and glycosyltransferases

- Allows for cell migration

Connective tissue disorders commonly caused by EMP dysfunction (joint flexibility)

- Collagenopathies including Ehlers-Danlos syndrome

Williams syndrome (elastin gene)

Marfan syndrome

Extracellular Matrix Proteins

Connective tissue disorders commonly caused by ______ dysfunction

and you will see ________ flexibility issues (leading to early onset arthritis)

EMP

joint