What is pleiotropism?
When one mutation manifests in many different physical ways.
What are some the the symptoms characteristic of Achondroplasia?
disproportionately short arms and legs
frontal bossing and mid-face hypoplasia.
Normal lifespan and IQ
What is the pathophysiology of Achondroplasia?
Mutations in FGFR3 (Autosomal Dominant)
→ FGF usually overstimulates bones to negatively regulate bone growth
→ With the mutation, FGFR is recycled back to the surface after down regulation
What happens when FGF binds to Receptor?
They dimerize and auto phosphorilate each other. It then has protein Kinase Activity.
How does an overstimulated FGF3 work?
FGF3 Receptor negatively regulates bone growth so the G380Receptor mutation results in constituitive activation of FGF Receptor. This causes decreased endochondral ossification, inhibited proliferation of chondrocytes, decreased cellular hypertrophy, and decreased cartliage matrix production.
What is the mechanism of what causes Achondroplasia?
It moves from G0 to G1 with the autophosphorilation of FGFR3. Adenine replaces guanine to cause the mutation. G1138A (99%) G1138C (1%)
Where is the location of the mutation for Achondroplasia.
What is the normal inheritance of Achondroplasia?
It is Autosoaml Dominant with 80% new mutations.
Who is the most likely contributor of the FGFR3 mutation to their child, the mother or the father?
(high mutation rate of sperm)
In Achondroplasia what happens when the infant has two mutations not jsut one?
homozygous individuals usually die before birth. They die of respiration failure due to small chest wall.
What are the genetic differences between hypochondroplasia, thanatophoric dysplasia, and achondroplasia?
Hypochondroplasia: Lys650 → Asn (large head micromelia)
Thanatophoric Dysplasia: Lys650 → Glu (lethal, it is a gain of fxn-active without the ligand present)
What causes Osteogenesis Imperfecta?
Overmodification of collagen and too many molecules being hydroxilated.
What is the inheritance of Osteogenesis Imperfecta Type I?
Which of the following is lethal?
OI Type I
What amino acid substitution causes the most severe problems in OI?
Arg, Asp, Valine
What ist he Amino Acid substitution that causes still borns in OI?
Asp for Glycine in Col1A1 gene.
You examine a patient with blue sclera and brown teeth. You suspect an autosomal dominant disease, what could this be?
Osteogenesis Imperfecta Type I (least severe)
(mutation in anything but glycine in collagen)
In OI, a mutation at what end of the transcript is worse?
C-terminal. This is the lethal (type II). Glycine are the worst.
N-terminus you see OI 1 and 4 (least severe types).
What is worse in OI, a mutation in the collagen α1 gene or the α2 gene?
(expresed 2x more)
What type of OI is the most lethal?
OI Type II
(glycine substitution) collagen can't form the triple helix
What type of OI will you see bowing of the femurs?
OI Type IV
What are the S/S of EDS IV?
this translucent skin, visible venous pattern, ....
What are the complications of EDS IV?
They can suffer arterial rupture, spontaneous rupture of the colon and rupture of gravid uterus when pregnant. This is the most lethal form of EDS.
What is the Ehlers-Danlos Syndrome triad?
Connective tissue fragility
EDS type 1 and 2 are caused by mutations in what type of collagen?
Type I & V (COL5A1, COL5A2, and COL1A1)
Which kind of EDS does not have flexible skin but is the most lethel form of EDS (collagen type 3 mutation)?
Type IV (AD- damages the protein structure) (COL3A1- affects pro-collagen synthesis)
Microcornea and recurrent intraocular bleeding w/ resultant blindness is characteristic of what EDS?
Type VI (AR-effects the enzyme)
defective lysyl hydroxylase gene, gets rid of the amine and adds OH to the cross-link.
What is defective in EDS Type VII?
conversion of type I procollagen to collagen
What are the S/S of EDS VI?
Soft hyperextensible skin, joint hypermobility, scoliosis, ocular fragidity, and marfanoid habitas. Also, recurrent intra-ocular bleeding with resultant blindness.
S/S of Marfans Syndrome?
tall stature, excessive length of estremities, mild pectus excavatum, myopia, mitral valve prolapse often present.
What are the two enzyme defects in EDS VII?
Defects in Exon 6- the domain that contains the cleavage site for N-Protease. and Defects in converting Enzyme pro-collagen-N-protease.
What is the Marfan's triad?
Arachnodactyly (spider fingers)
Ectopic lentis (displaced lens)
Aortic aneurysm (aorta rupture)
In Marfan's syndrome over 40% of mutations result in what amino acid substitution?
another amino acid for a cystein
What is the inheritance pattern of Marfans?
Autosomal Dominant negative
the defective glycoprotein product of the fibrillin gene antagonizes the product of the normal allele
What gene is defective in Marfan's syndrome?
Fibrillin (FBN1)- it is invovled in interconnectivity and elasticity of CT.
In Marfan's, is it better to have a missense, frameshift or nonsense mutation?
Frameshift or nonsense (missense mutations dont reduce teh concentration of mutated protein.
Other than Marfan's triad, what other physical findings may be present?
tall stature, excessive long limbs
mild pectus excavatum
mitral valve prolapse