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Genetics > L14 Developmental Genetics > Flashcards

L14 Developmental Genetics Flashcards

1
Q

What are the 2 classifications of developmental defects?

A

single abnormalities

multiple abnormalities

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2
Q

what 4 things make up single abnormalities?

A

malformation
disruptions
deformations
dysplasias

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3
Q

what is malformation and what are examples?

A

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

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4
Q

what is disruptions and what are examples?

A

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

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5
Q

what is deformations and what are examples?

A

mechanical distortion
usually resolve soon after birth

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

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6
Q

what is dysplasia and what are examples?

A

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

thanatophoric dysplasia - FGF3R mutation that affects almost all the skeleton

*most are monogenic - GENETIC

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7
Q

what 3 things make up multiple abnormalities?

A

sequences
syndromes
associations

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8
Q

what are sequences and what are examples?

A

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

Potter sequence - due to decreased amniotic fluid

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9
Q

what are syndromes and what are examples?

A

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

Down syndrome - due to trisomy 21

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10
Q

what are associations?

A

traits occur more often than expected by chance

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11
Q

what is sonic hedgehog genes (SHH)?

A

induce cell proliferation - involved in tissue patterning

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12
Q

what are the functions of SHH?

A
  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)
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13
Q

define modifier effect

A

genetic background somehow influences the severity/expressivity of SHH mutation

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14
Q

where is the location of SHH gene in humans?

A

long arm of chromosome 7 (7q36)

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15
Q

what does heterozygous mutations of SHH result in?

A

one form of autosomal dominant holoprosencephaly (HPE3)

*wide clinical variability

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16
Q

what are the possible variable clinical presentations seen in holoprosencephaly?

A
  • facial abnormalities (cyclopia, premaxillary agenesis, mild hypotelorism = close eyes, single central maxillary incisor)
  • mild microcephaly alone
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17
Q

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

A

preaxial polydactyly

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18
Q

what does increasing SHH in the frontal nasal prominence promote?

A

mediolateral expansion of the face and ventral forebrain = HYPERtelorism

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19
Q

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

A

rare

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20
Q

what are the functions of HOX genes?

A

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

gives identity to cells/body segments

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21
Q

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

A

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

22
Q

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

A

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

23
Q

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

A

polydactyly

24
Q

what is holoprosencephaly - incidence, defect, symptoms

A

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
25
Q

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

A

1/20,000 - 1/40,000 births

mutation in 7-dehydrocholesterol reductase

-microcephaly, mental retardation, malformation of mesodermal origin, syndactyly, and polydactyly

26
Q

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

A

1/56,000 - 1/164,000

mutation in patched (PTC)

  • early age basal cell carcinoma (< 20 years)
  • rib defects
27
Q

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

A

extremely RARE

mutation in Gli genes

-brain tumors, polydactyly

28
Q

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

A

1/125,000 births

mutation in the CREBBP gene

broad thumbs and toes, mental disability, short stature, small heads, facial features

29
Q

what establishes the patterning of anterior/posterior body axis?

A

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!

30
Q

_____ interactions are important for transcription factor function

A

protein

31
Q

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

A

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

32
Q

dimer formation adds what?

A

extra element of complexity and versatility

*zinc finger, helix-turn-helix, leucine zipper

33
Q

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

A

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

34
Q

what is homologous transformation - just give example

A

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

35
Q

child with extra cervical rib have a higher frequency of?

A

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

36
Q

what is polydactyly and what gene has the mutation

A

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

37
Q

what are the symptoms of achondroplasia?

A

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)
38
Q

what is Achondroplasia - inheritance, incidence, defect, symptoms

A

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

39
Q

what is the function of the FGFR3 gene

A

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

40
Q

what stages do chondrocytes develop through

A

reserve
proliferating
hypertropic

41
Q

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

A

gain of function mutations

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

42
Q

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

A

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…

43
Q

Describe how mitotic drive may cause achondroplasia?

A

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

44
Q

define locus heterogeneity

A

different mutations cause different phenotypes

locations of common mutations in the FGFR3

45
Q

List mutations in FGFR3 gene from most severe to least severe

A

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

46
Q

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

A

involved in XY pairing during cytokinesis and metaphase

can get crossover here too

47
Q

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

A

male gender

48
Q

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

A

develops into ovaries

49
Q

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

A

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
50
Q

describe 46, XY Swyer Syndrome (pure gonadal dysgenesis)

A

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

Genetics (15 decks)

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