L14 Developmental Genetics Flashcards
What are the 2 classifications of developmental defects?
single abnormalities
multiple abnormalities
what 4 things make up single abnormalities?
malformation
disruptions
deformations
dysplasias
what is malformation and what are examples?
due to errors in the initial formation of structures
a primary structural defect of an organ or part of an organ
congenital heart abnormalities
cleft lip
cleft plate
polydactyly
*most are multifactoral - have genetic + environmental component
what is disruptions and what are examples?
due to disturbances after an organ has been formed
abnormal structure of an organ or tissue as a result of external forces (not genetics)
phocomelia - shortened arms or legs that result from a vascular problem
what is deformations and what are examples?
mechanical distortion
usually resolve soon after birth
clubfoot - caused by lack of amniotic fluid or intra-uterine crowding (physical force on fetus)
what is dysplasia and what are examples?
abnormalities in tissue organization (at the level of the tissue)
thanatophoric dysplasia - FGF3R mutation that affects almost all the skeleton
*most are monogenic - GENETIC
what 3 things make up multiple abnormalities?
sequences
syndromes
associations
what are sequences and what are examples?
cascades of effects (maybe one single defect leads to a series of problems)
Potter sequence - due to decreased amniotic fluid
what are syndromes and what are examples?
single cause leads to a group of anomalies (that all usually occur together)
Down syndrome - due to trisomy 21
what are associations?
traits occur more often than expected by chance
what is sonic hedgehog genes (SHH)?
induce cell proliferation - involved in tissue patterning
what are the functions of SHH?
- Dorsal ventral patterning
- development of hair follicle, tooth, lung and pancreas
- limb patterning - zone of polarizing activity (ZPA) (in anterior posterior axis of limb)
define modifier effect
genetic background somehow influences the severity/expressivity of SHH mutation
where is the location of SHH gene in humans?
long arm of chromosome 7 (7q36)
what does heterozygous mutations of SHH result in?
one form of autosomal dominant holoprosencephaly (HPE3)
*wide clinical variability
what are the possible variable clinical presentations seen in holoprosencephaly?
- facial abnormalities (cyclopia, premaxillary agenesis, mild hypotelorism = close eyes, single central maxillary incisor)
- mild microcephaly alone
what is the result of ectopic expression of SHH in the anterior limb bud?
preaxial polydactyly
what does increasing SHH in the frontal nasal prominence promote?
mediolateral expansion of the face and ventral forebrain = HYPERtelorism
true facial duplications are very ___ in humans suggesting that they may be associated with other developmental disturbances that are incompatible with life.
rare
what are the functions of HOX genes?
pattern the anterior-posteior axis of vertebrae embryo and limb bud
gives identity to cells/body segments
in the limb bud, how is HOX gene expression established?
generation of a SHH gradient produced by the zone of polarizing activity (ZPA)
where is there high and low concentrations of SHH in the limb bud?
low - thumb
high - pinky
so in immunologic stain? you see lots of ZPA in hindlimb where pinky is and only a little ZPA brightness in forelimb
mutations affecting expression (over expression) of SHH in the limb bus + mutation in Gli3 can lead to ?
polydactyly
what is holoprosencephaly - incidence, defect, symptoms
1/5,000 to 1/10,000 live birth
mutation in the SHH or the Six3gene (which is a regulator of SHH)
There is NO correlation between a specific mutation and SHH and a phenotype manifestation (modifier effects)!
spectrum of defects/disorders
- mild = single incisor
- moderate = cleft lip and palate
- severe = cyclopia
what is Smith-Lemi-Opitz Syndrome - incidence, defect, symptoms
1/20,000 - 1/40,000 births
mutation in 7-dehydrocholesterol reductase
-microcephaly, mental retardation, malformation of mesodermal origin, syndactyly, and polydactyly
what is Gorlin syndrome (nevoid basal cell carcinoma) - incidence, defect, symptoms
1/56,000 - 1/164,000
mutation in patched (PTC)
- early age basal cell carcinoma (< 20 years)
- rib defects
what is Pallister-Hall Syndrome - incidence, defect, symptoms
extremely RARE
mutation in Gli genes
-brain tumors, polydactyly
what is Rubinstein-Taybi syndrome - incidence, defect, symptoms
1/125,000 births
mutation in the CREBBP gene
broad thumbs and toes, mental disability, short stature, small heads, facial features
what establishes the patterning of anterior/posterior body axis?
overlapping domains of Hox gene expression
*the 5’ end is the anterior region
the 3’ end is the posterior region
*they are obviously important if they survived evolution in many species!
_____ interactions are important for transcription factor function
protein
transcription factors are modular in their structure: one part of the protein is for ____, another is for ___ and another is for ____
DNA binding
dimer formation
transcriptional activation (interaction with basal transcription machinery)
dimer formation adds what?
extra element of complexity and versatility
*zinc finger, helix-turn-helix, leucine zipper
what is the difference between humans and fruit fly Hox genes?
fruit flies have one Hox gene, so if it is mutated, there are serious phenotypical manifestations = many wings etc.
humans have many Hox genes (paraligous groups), so you won’t see severe manifestations with mutations - you would have to knock out an entire paraligous group
what is homologous transformation - just give example
in fruit fly - its abdominal segment takes on identity of thorax and grows wings so now it has 2 wings
in a mouse, the axis thickens and takes on the identity of the atlas
human - extra cervical rib
child with extra cervical rib have a higher frequency of?
childhood cancer - if they don’t survive, they can’t reproduce. therefore, the Hox mutation will not be passed down into the population = developmental constraint
what is polydactyly and what gene has the mutation
having more than the normal number of fingers or toes
distruption (due to disturbances after an organ has been formed abnormal structure of an organ or tissue as a result of external forces (not genetics)) of Hox d 13 gene
what are the symptoms of achondroplasia?
abnormal body proportions
- short arms and legs with normal torso
- reduced height
- typically upper arms and thigh are more shortened than forearms and lower legs
facial features
- large head
- flat nose bridge
hand features
- shortened and stubby fingers
- trident hand (big space between fingers)
what is Achondroplasia - inheritance, incidence, defect, symptoms
full penetrance, autosomal dominant
1/10,000 - 1/40,000 births
mutation in the fibroblast growth factor receptor 3 (FGFR3) gene
result in stimulation of chondrocyte growth and prevents differentiation to bone and the growth plate at epiphysis
normal LE
80% of cases = spontaneous mutation during spermatogenesis (old dad)
20% of cases = inheriting a mutation from 1 parent
what is the function of the FGFR3 gene
inhibit chondrocyte growth and differentiation in the growth plate of developing long bones
what stages do chondrocytes develop through
reserve
proliferating
hypertropic
what type of mutation is FGFR3 gene that results in achondroplasia? why?
gain of function mutations
causes a decrease in chondrocyte differentiation and the formation of osteoblasts (Ob)
what do almost all cases of achondroplasia involve a mutation of? Describe the mutation
FGFR3 gene with a G-C transversion at NT 1138
substitute arginine residue for a glycine at position 360 of FGFR3 protein
located in transmembrane domain
this site has one of the highest mutation rates in the human genome (located at CpG site and appears to be affected by other chromosomal translocations)
this maybe an artifact of sperm with FGFR3 mutations having selective advantage…
Describe how mitotic drive may cause achondroplasia?
sperm that has mutation has a selective advantage over the sperm that do not - mutation occurs during miosis and mitosis of promordial germ cells
define locus heterogeneity
different mutations cause different phenotypes
locations of common mutations in the FGFR3
List mutations in FGFR3 gene from most severe to least severe
thanatophoric dysplasia (TD)
SADDAN dysplasia
achondroplasia (ACH)
hypochondroplasia (HYP)
what is the importance of the pseudo autosomal region of the Y chromosome
involved in XY pairing during cytokinesis and metaphase
can get crossover here too
what does the presence of SRY gene determine (SRY produces testes determining factor TDF)
male gender
if the Y chromosome is absent, what happens to gonadal primordia (has Mullerian duct and Wolfian ducts)
develops into ovaries
describe 46, XX male syndrome (de la Chapelle syndrome) - incidence, mutation, features
1/20,000 males
translocation of SRY gene onto X chromosome
genotype = XX, but one X has SRY
features
- boys and men pretty much normal expect…
- 10% have hypospadias
- infertility because asospermiofactor genes are not there
describe 46, XY Swyer Syndrome (pure gonadal dysgenesis)
1/80,000 births
genotype = XY but SRY gene is mutated and non function (loss of function)
features
- normal female but has bilateral streak gonads instead of ovaries or testes
- early puberty onset
- elevated PH = cliotomegaly
Tx - remove streak gonad because increased chance of germline tumors
hormone replacement with estrogen/progesterone
DO NOT CONFUSE WITH FEAT OF ANDROGEN INSENSITIVITY - this is mutation of SRY, not androgen receptor
