errors occurring in the initial formation of structures like cleft lip or polydactyly
malformation
disturbances after an organ has been formed due to external forces and not genetics like shortened arms or legs due to vascular problem
disruptions
mechanical distortions like club foot due to lack of amniotic fluid
deformation
abnormalities in tissue organization like thanatophoric dysplasia
dysplasia
cascades of effects
sequences
groups of anomalies that consistently occur together due to a single underlying cause
syndromes
traits coincide more often than expected with chance
association
induces cell proliferation and involved in tissue patterning
sonic hedgehog genes
type of patterning in sonic hedgehog genes
dorsal ventral patterning
sonic hedgehog derived from
neural ectoderm such as notochord and ventral floor plate of neural tube
zone of polarizing activity for sonic hedgehog genes
limb patterning
sonic hedgehog involved in the development of what
hair follicles, tooth, lung, pancreas
what role does sonic hedgehog play in the patched gli pathway
it binds to the PTCH and relieves the inhibition of SMO therefore activating downstream signaling
what inhibits SMO in the patched gli pathway
PTCH
how is sonic hedgehog prepared or modified before it binds to the PTCH
it is cleaved to an active N terminal form then cholesterol is added to it
what happens when the Gli protein and CREBBP interact in the PTCH gli pathway
they activate gene expression by binding to the regulatory sequence on DNA
where is SHH located on humans
distal long arm of chromosome 7
heterozygous mutation of SHH results in what?
autosomal dominant holoprosencephaly
clinical variability in people that present with holoprosencephaly
facial abnormalities (cyclopia, premaxillary agenesis, mild hypotelorism, or a single central maxillary incisor) to mild microcephaly alone.
increased SHH in the frontal nasal prominence that promotes mediolateral expansion of the face and ventral forebrain
hypertelorism
what does HOX gene pattern
anterior-posterior of the vertebrate embryo and limb bud
what activated HOX gene expression
gradient of SHH which is created by ZPA (zone polarizing activity)
what leads to polydactyly
overexpression of SHH in the limb bud and mutation in the Gli3
holoprosencephaly is caused by a mutation where
in the SHH or Six3 gene
mild effects such as single incisor, moderate effects such as cleft lip and palate, to severe effects such as cyclopia are all what?
variability in SHH mutation (SN: there is no correlation between specific mutation in SHH and phenotype)
mutation in 7 dehydrocholesterol reductase
Smith Lemi Optiz Syndrome (SLOS)
SLOS phenotype
microcephaly, mental retardation, malformation of mesodermal origin, syndactly, and polydactyly
mutation in patched (ptc)
gorlin syndrome (nevoid basal cell carcinoma)
rare mutation in gli gene
pallister hall syndrome (brain tumors and polydactyly)
mutation in CREBBP gene
Rubinstein-Taybi Syndrome
broad thumbs and toes, mental disability, short stature, small head, facial features
mutation in CREBBP gene
patterning of anterior posterior body axis is done by
overlapping HOX gene expression
what happens if there is a mutation in the hox genes in fruit fly
unusual transformation of body segment identity
why doesn’t a mutation in mammalian hox genes show dramatic changes
because we have other hox genes/clusters that will come in and take the place of a mutated one
in humans what happens if there is a single loss of a hox gene
it increases childhood susceptibility to leukemia
what must be done to see a dramatic change in mammalians
must completely knock out all the hox genes in that area
children with extra cervical rib have a higher frequency for cancer than general population so what does that mean
low reproductive fitness
polydactyly is a result of what
disruption in hoxd13 gene
achondroplasia is a result of mutation where
FGFR3 (fibroblast growth factor receptor 3) with a G-C transversion at nucleotide 1138 ath the transmembrane domain
80% of achondroplasia is due to what?
80% - spontaneous mutation during spermatogenesis
20% - inherited from one parent
how do chondrocytes develop
sequentially through reserve (R), proliferating (P), prehypertropic (PH), and hypertropic stages
function of FGFR3
inhibit chondrocyte growth and differentiation in the growth plate of developing long bones
in achondroplasia, there is a substitution of what and where
arginine replaced with glycine at position 360 on the FGFR3 protein
less severe to most severe mutation of FGFR3 mutation
hypochondroplasia, achondroplasia, SAADAN dyplasia, thanatophoric dysplasia
hypochondroplasia is mutation where
proximal (more common) and distal tyrosine kinase domain
thanatophoric dysplasia is mutation where
extracellular domain and distal tyrosine kinase domain (lethal)
what is deleted in infertile male
Regions AZFa, b, c (azoospermia factor)
what happens in presence and absence of Y chromosome
presence - testes develop
absence - ovaries develop
gonadal differentiation is determined by
presence or absence of SRY gene located on Y chromosome that produces testis determining factor (TDF)
what does testis produce
anti mullerian duct hormone that destroys mullerian duct and testosterone
46 XX Male sydrome (de la Chapelle syndrome) is caused by what
translocation of the SRY gene on the Y chromosome due to unequal crossing over during meiosis (Y translocated onto X)
characteristics of de la chapelle syndrome
10% hypospadias, mullerian tissue absent, short, infertile
46 XY female Swyer syndrome (pure gonadal dysgenesis) is caused by
loss of function mutation of SRY gene
characteristics of Swyer syndrome
normal femae genitalia, mullerian ducts present, LH increased so clitoromegaly, bilateral streak gonads instead of ovaries or testes, delayed puberty
treatment of swyer syndrome
estrogen and progesterone, streak gonads removed
polymorphic markers on Y chromosome has been used to trace whom
human from their migration from Africa