Developmental Genetics Flashcards
1
Q
Single Abnormalities:
A
- Malformations: errors occurring in the initial formation of structures, primary structural defect of an organ. (congenital heart abnl, cleft lip/palate, polydactyly). Multifactorial.
- Disruptions: disturbances after an organ has been formed; result of external force not genetics. (Phocomelia “shortened arms/legs”
- Deformations: mechanical distortions (clubfoot by lack of amniotic fluid or intra-uterine crowding). Resolves after birth.
- Dysplasias: abnormalities in tissue org (thanatophoric dysplasia “FGF3R mutation”). Monogenic.
2
Q
Multiple abnormalities
A
- Sequences: cascades of effects (Potter seq due to decr. amniotic fluid)
- Syndromes: grp of anomalies that consistently occur together due to a single underlying cause “Down synd”
- Associations: traits coincide more often than expected
3
Q
SHH
A
- induces cell prolif and tissue patterning
- expressed in: neural ectoderm like notochord and ventral floor plate of NT = dorsal -> ventral patterning
- hair follicle, tooth, lung and pancreas devlp.
- Zone of polarizing activity ZPA=> limb patterning
4
Q
SHH-Ptch-Gli pathway
A
- Shh is cleaved to an N-terminal form (N-SHH) -> modified by addition of cholest.
- nl action of Ptch is to inhibit Smo. But when Ptch bound by SHH = inhibition removed.
- Gli protein and CREBBP interact and activate gene exp by binding to regulatory seq. on DNA
(overexpression of SHH in limb bud or mutation in Gli3 lead to polydactyly)
5
Q
SHH mutations
A
- heterozygous mutation of SHH = autosomal dom. Holoprosencephaly (HPE3) = wide clinical variability such as: cyclopia, premaxillary agenesis, mild hypotelorism or single central maxillary incisor to microcephaly.
- polydactyl could result from ectopic exp of Shh in ant. limb bud.
- Rare in humans but incr. SHH in frontal nasal prominence promotes mediolateral expansion “hypertelomerism”
6
Q
Holoprosencephaly
A
- mutation in SHH or Six3 gene(regulator of Shh)
- modifier effects: a spectrum of defects and disorders.
- mild effects: single incisor
- moderate: cleft lip/palate
- severe: cyclopia
7
Q
Smilth-Lemi-Opitz syndrome
A
- mutation in 7-dehydrocholesterol reductase
- microcephaly, mental retardation, malformation of mesodermal origin, syndactly and polydactly
8
Q
Gorlin syndrome (Nevoid basal cell carcinoma)
A
- mutation in Patched “Ptch”
- early age basal cell carcinoma
9
Q
Pallister-Hall syndrome
A
- rare
- mutation in Gli genes
- brain tumors, polydactyl
10
Q
Rubinstein-Taybi syndrome
A
- mutation in the CREBBP gene
- broad thumbs and toes, mental disability, short stature, small head and facial features
11
Q
Hox genes
A
- TFs that confer identity to indiv body segments.
- patterning of ant/post or body axis
- mutations in mammalian Hox genes = no dramatic phenotype b/c there are many copies of Hox genes. Must have a complete knockout to see phenotype.
- loss of single Hox gene in humans = incr. susceptibility to childhood leukemia w/ extra cervical ribs.
- Disruption of Hoxd13 = polydactyly
12
Q
Achondroplasia
A
- AD, full penetrance
- mutation in transmemb domain of FGFR3 = stimulation of chondrocyte growth and prevents diff to bone and formation of osteoblast.
- GoF mutation, G-C transversion “substitution of Arg for Glyc”
- 80% of cases as a result of spont mutation during spermatogenesis “sperm w/ selective adv”
- 20% of cases result of inheriting.
- abnl body proportions (upper arms/thighs more shortened than forearms and lower legs.
- large head, flat nasal bridge, trident hand
13
Q
Severity of Achond:
-severe to less severe?
A
-Thanatophoric dysplasia > SADDAN dysp > Achondroplasia > Hypochondroplasia
14
Q
Thanatophoric dysplasia (TD)
A
- mutation in EC domain and distal tk domain.
- severe: similar to homoz achond “lethal”
- short limbs, narrow chest, small ribs, undevlp lungs, enlarged head.
- usually still born or die after birth.
15
Q
ACH
A
- mutation in transmemb domain
- intermediate severity
- nl lifespan
- enlarged skull, short and flattened vertebral disks.
