L14 Developmental Genetics

Question 1

What are the 2 classifications of developmental defects?

Answer 1

single abnormalities

multiple abnormalities

Question 2

what 4 things make up single abnormalities?

Answer 2

malformation
disruptions
deformations
dysplasias

Question 3

what is malformation and what are examples?

Answer 3

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

Question 4

what is disruptions and what are examples?

Answer 4

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

Question 5

what is deformations and what are examples?

Answer 5

mechanical distortion
usually resolve soon after birth

clubfoot - caused by lack of amniotic fluid or intra-uterine crowding (physical force on fetus)

Question 6

what is dysplasia and what are examples?

Answer 6

abnormalities in tissue organization (at the level of the tissue)

thanatophoric dysplasia - FGF3R mutation that affects almost all the skeleton

*most are monogenic - GENETIC

Question 7

what 3 things make up multiple abnormalities?

Answer 7

sequences
syndromes
associations

Question 8

what are sequences and what are examples?

Answer 8

cascades of effects (maybe one single defect leads to a series of problems)

Potter sequence - due to decreased amniotic fluid

Question 9

what are syndromes and what are examples?

Answer 9

single cause leads to a group of anomalies (that all usually occur together)

Down syndrome - due to trisomy 21

Question 10

what are associations?

Answer 10

traits occur more often than expected by chance

Question 11

what is sonic hedgehog genes (SHH)?

Answer 11

induce cell proliferation - involved in tissue patterning

Question 12

what are the functions of SHH?

Answer 12

1. Dorsal ventral patterning
2. development of hair follicle, tooth, lung and pancreas
3. limb patterning - zone of polarizing activity (ZPA) (in anterior posterior axis of limb)

Question 13

define modifier effect

Answer 13

genetic background somehow influences the severity/expressivity of SHH mutation

Question 14

where is the location of SHH gene in humans?

Answer 14

long arm of chromosome 7 (7q36)

Question 15

what does heterozygous mutations of SHH result in?

Answer 15

one form of autosomal dominant holoprosencephaly (HPE3)

*wide clinical variability

Question 16

what are the possible variable clinical presentations seen in holoprosencephaly?

Answer 16

• facial abnormalities (cyclopia, premaxillary agenesis, mild hypotelorism = close eyes, single central maxillary incisor)
• mild microcephaly alone

Question 17

what is the result of ectopic expression of SHH in the anterior limb bud?

Answer 17

preaxial polydactyly

Question 18

what does increasing SHH in the frontal nasal prominence promote?

Answer 18

mediolateral expansion of the face and ventral forebrain = HYPERtelorism

Question 19

true facial duplications are very ___ in humans suggesting that they may be associated with other developmental disturbances that are incompatible with life.

Answer 19

rare

Question 20

what are the functions of HOX genes?

Answer 20

pattern the anterior-posteior axis of vertebrae embryo and limb bud

gives identity to cells/body segments

Question 21

in the limb bud, how is HOX gene expression established?

Answer 21

generation of a SHH gradient produced by the zone of polarizing activity (ZPA)

Question 22

where is there high and low concentrations of SHH in the limb bud?

Answer 22

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

Question 23

mutations affecting expression (over expression) of SHH in the limb bus + mutation in Gli3 can lead to ?

Answer 23

polydactyly

Question 24

what is holoprosencephaly - incidence, defect, symptoms

Answer 24

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

Question 25

what is Smith-Lemi-Opitz Syndrome - incidence, defect, symptoms

Answer 25

1/20,000 - 1/40,000 births mutation in 7-dehydrocholesterol reductase -microcephaly, mental retardation, malformation of mesodermal origin, syndactyly, and polydactyly

Question 26

what is Gorlin syndrome (nevoid basal cell carcinoma) - incidence, defect, symptoms

Answer 26

1/56,000 - 1/164,000 mutation in patched (PTC) - early age basal cell carcinoma (< 20 years) - rib defects

Question 27

what is Pallister-Hall Syndrome - incidence, defect, symptoms

Answer 27

extremely RARE mutation in Gli genes -brain tumors, polydactyly

Question 28

what is Rubinstein-Taybi syndrome - incidence, defect, symptoms

Answer 28

1/125,000 births mutation in the CREBBP gene broad thumbs and toes, mental disability, short stature, small heads, facial features

Question 29

what establishes the patterning of anterior/posterior body axis?

Answer 29

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!

Question 30

_____ interactions are important for transcription factor function

Answer 30

protein

Question 31

transcription factors are modular in their structure: one part of the protein is for ____, another is for ___ and another is for ____

Answer 31

DNA binding dimer formation transcriptional activation (interaction with basal transcription machinery)

Question 32

dimer formation adds what?

Answer 32

extra element of complexity and versatility *zinc finger, helix-turn-helix, leucine zipper

Question 33

what is the difference between humans and fruit fly Hox genes?

Answer 33

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

Question 34

what is homologous transformation - just give example

Answer 34

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

Question 35

child with extra cervical rib have a higher frequency of?

Answer 35

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

Question 36

what is polydactyly and what gene has the mutation

Answer 36

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

Question 37

what are the symptoms of achondroplasia?

Answer 37

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)

Question 38

what is Achondroplasia - inheritance, incidence, defect, symptoms

Answer 38

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

Question 39

what is the function of the FGFR3 gene

Answer 39

inhibit chondrocyte growth and differentiation in the growth plate of developing long bones

Question 40

what stages do chondrocytes develop through

Answer 40

reserve proliferating hypertropic

Question 41

what type of mutation is FGFR3 gene that results in achondroplasia? why?

Answer 41

gain of function mutations causes a decrease in chondrocyte differentiation and the formation of osteoblasts (Ob)

Question 42

what do almost all cases of achondroplasia involve a mutation of? Describe the mutation

Answer 42

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...

Question 43

Describe how mitotic drive may cause achondroplasia?

Answer 43

sperm that has mutation has a selective advantage over the sperm that do not - mutation occurs during miosis and mitosis of promordial germ cells

Question 44

define locus heterogeneity

Answer 44

different mutations cause different phenotypes locations of common mutations in the FGFR3

Question 45

List mutations in FGFR3 gene from most severe to least severe

Answer 45

thanatophoric dysplasia (TD) SADDAN dysplasia achondroplasia (ACH) hypochondroplasia (HYP)

Question 46

what is the importance of the pseudo autosomal region of the Y chromosome

Answer 46

involved in XY pairing during cytokinesis and metaphase | can get crossover here too

Question 47

what does the presence of SRY gene determine (SRY produces testes determining factor TDF)

Answer 47

male gender

Question 48

if the Y chromosome is absent, what happens to gonadal primordia (has Mullerian duct and Wolfian ducts)

Answer 48

develops into ovaries

Question 49

describe 46, XX male syndrome (de la Chapelle syndrome) - incidence, mutation, features

Answer 49

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

Question 50

describe 46, XY Swyer Syndrome (pure gonadal dysgenesis)

Answer 50

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