What do FGFs do?
With their receptors, they regulate cell proliferation, migration, and differentiation. In adults they function in response to injury.
What is Achondroplasia characterized by
Short Stature, dispropotionately short arms and legs, large head, characteristic facial features. IQ is usually normal. Normal life span, but increased risk in infancy due to compression of spinal cord or upper airway.
What is the most common mutation leading to Achondroplasia?
Mutation in Fibroblast Growth Factor Receptor Gene 3 aka FGFR3. This is specifically G1138A meaning G at the 1138 nucleotide is replaced by an A (or G380R yields the same thing). In the most rare cases it can be replaced by a C. This is the highest mutation rate known.
What are the direct structural effects of this mutation?
Abnormal Cartilage and Fibrous CT tissue formation. All bones, liaments, tendons, and muscles are affected.
What type of inheritance does Achondroplasia have?
Autosomal Dominant and it does not skip a generation. It is prevalent in both males and females. 80% are new mutations with 100% penetrance. Homozygous individuals die before birth.
What type of mutation is the G380R mutation? What happens?
It is a gain of function mutation that results in constitutive activation of the FGF receptor. FGFR3 normally negatively regulates bone growth, so it will be broken in this mutation. With it broken, there will be decreased ossification, inhibited proliferation of chondrocytes, decreased hypertrophy, and decreased cartilage matrix production.
What other mutations can occur due to a mutation if FGFR3?
Hypochondroplasia and Thenatophoric Dysplasia
What is Hypochondroplasia?
A mutation leading to short stature, micromelia (short limbs), and a large head. The mutation is G1950T/C also called Lys650Asn
What is Thenatophoric Dysplasia?
Lethal FGFR3 receptor mutation that leads to gain of function mutant that is active in the absence of a ligand. There is extremely short limbs with extra skin folds. This is always lethal and the most common lethal neonatal dwarfism.
Describe the structure of collagen and important facets of its creation:
With collagen, every 1/3 amino acids is Glycine. Glycines allow the collagen fibers to closely pack together. The tight packing prevents overly modified collagens. In its creation, the N- and C- terminuses are cleaved in order to associate tropocollagen into collage fiber. The Triple Helix starts wrapping together at the C terminus of the three collagen molecules. These fibers form cross links.
What are the mutation sites targeting collagen?
Mutations in the collagen gene itself and mutations in the enzymes that process the collagen protein.
What is Osteogenesis Imperfecta Type 1?
An autosomal dominant disease with a mutation in amino acids in the collagen other than glycine. It effects mostly type 1 collagen. There is little or no deformity. Patients present with a blue sclera. Mutations of the alpha1 gene are worse than the alpha 2 gene since alpha 1 is expressed more.
Discuss Type II Osteogenesis Imperfecta:
It is lethal. The mutation is usually in the C terminus. The mutations are due to lethal substitutions of Glycine.
Discuss Type III Osteogenesis Imperfecta:
It is not lethal. There is progressive deformity after birth. This is due to a Gly-526-Cys substitution.
Which mutations causing Osteogenesis Imperfecta are the worst?
Glycine Substitutions are the worst. C Terminus mutations are worse than N terminus mutations. Since Alpha1 gene is expressed more, a mutation there is worse than Alpha2(this is in OI Type 1).
What is the "Triad" of Ehlers-Danlos Syndrome?
Hyperextensibility, Joint Hypermobility, and Connective Tissue Fragility
What are the inheritance patterns of Ehlers-Danlos?
Autosomal Dominant for mutations in the structural protein. Autosomal Recessive for the enzyme.
What types of EDS are associated with type V collagen? What are the mutations?
Types I and II (the classical EDS). COL5A1/COL5A2 (this means Collagen V, Alpha1 or 2)
What is Vascular Type ED Syndrome VEDS?
Also EDS Type IV, this is caused by a COL3A1 mutation that affects collagen type III. It leads to venous pattern over the trunk, translucent skin. Major complications are arterial rupture, rupture of the colon, and rupture of the uterus when pregnant. This is the most lethal EDS. Thereis NO hyperflexibility,hypermobility of joints or skin.
What is EDS Type VI?
An Autosomal Recessive disease due to defects in Lysyl Hydroxylase gene. There is soft hyperextensible skin, joint hypermobility, scoliosis, ocular fragility, and a "marfanoid habitas." There is Microcornea and recurrent intraocular bleeding with blindness.
What is EDS Type VII?
An Autosomal Recessive disease due to defects in the conversion of type 1 pro-collagen to collage due to either deletions of exon 6 (cleavage site for N-protease) OR in the Procollagen N-Protease.
What is the triad of Marfan's syndrome?
Arachnodatylyl (Spider Fingers), Ectopic Lentis (displaced lens), and Aortic Aneurysm.
What are the gentics behind Marfan's Syndrome?
Autosomal Dominant and the mutation is in Fibrillin.
What is Fibrillin normally involved with?
The interconnectivity and elasticity of connective tissue.
What are the clinical presentations of Marfan Syndrome?
Tall Stature, Excessively lengthened upper and lower extremities, mild pectus excavatum, and myopia. There is often Mitral Valve Prolapse. This disease is an example of Pleiotropism.
What is the usual gene mutation behind Marfan syndrome?
Marfan Syndrom has a Fibrillin problem. This is called a mutation in FBN 1. There is usually a substitution of an amino acid for a cysteine (40%). Less mutations are better (duh) and this is considered a "Dominant Negative Mutation."
Explain the "less is better" aka Dominant Negative Mutations:
If the mutation leads to a premature termination codon, ten LESS of the bad gene will be made and the disease will have a less severe form. This would be more ideal in Marfan syndrome than a "missense" mutation.