Autosomal Dominant Disorders Flashcards
In what ways can dominant mutations cause disease?
- Loss of function: haploinsufficiency and dominant negative
- Gain of function
Haploinsufficiency
- Cause of autosomal dominant disease
- When a half dosage of a normal gene product is insufficient for normal functionality
Dominant negative
- Cause of autosomal dominant disease
- When the half dosage of abnormal gene product causes MORE than half reduction in functionality
What kind of disorder is familial hypercholesterolemia?
- Autosomal dominant caused by haploinsufficiency
What is the cause of familial hypercholesterolemia?
- Insufficient LDL receptors (haploinsufficiency)
What are symptoms of familial hypercholesterolemia?
- Fatty deposits in skin and blood vessels => life expectancy < 20
What kind of disorder is caused by insulin Chicago?
Dominant negative: heterozygotes get diabetes
Describe the mutation and altered functionality of insulin Chicago.
- Phe>Leu near B-chain C-ter
- Binds to insulin receptors (preventing normal insulin binding) but does not promote glucose uptake
How can a mutation to a subunit of a protein dimer have a dominant negative effect?
- A and B subunits can form AA, AB, or BB dimers in 1:2:1 ratio
- If one subunit is mutated such that it can still bind the other but is nonfunctional, 3/4 of the dimers will be nonfunctional
Collagen
- Extracellular proteins that are a component of connective tissue
How is collagen synthesized?
- alpha-1 chains and alpha-2 chains synthesized
- 2 alpha-1 chains and 1 alpha-2 chain spontaneously assemble into triple helix
- N and C ter’s removed
- helices associate and bind
What is the mechanism of osteogenesis imperfecta?
Protein suicide (dominant negative)
How can a mutant collagen alpha-1 allele cause protein suicide?
- 2 normal alpha-1 and normal alpha-2 can associate to make normal collagen
- 1 or 2 abnormal alpha-1 collagen can associate with normal alpha-2 to make abnormal collagen destined for degradation (or decreased functionality)
- only 1/4 functional collagen
Why does osteogenesis imperfect have variable clinical severity?
- Some mutations will decrease synthesis or increase degradation but maintain normal collagen structure => mild phenotype
- Some mutations (like IF indels) will alter structure => more severe phenotype
What are symptoms of osteogenesis imperfecta?
- frequent fractures
- blue sclera
What are the symptoms of Ehlers-Danlos syndrome?
- hyperelastic, fragile, soft, velvety skin
- skins tears and bruises easily forming “cigarette paper” scars
- joint hypermobility and dislocations
- mitral valve prolapse
- hiatal hernia and anal prolapse
- flat feet
- infancy: hypotonia and delated motor milestones
What is the mechanism of EDS?
- haploinsufficiency of type 5 collagen
What mutations cause EDS?
type 5 collagen mutations generating a null allele
What are the symptoms of achondroplasia?
- Small stature
- disproportionate shortening of proximal limb segments
- short skull base with large head
- spinal stenosis
- normal intelligence
- accentuated lumbar lordosis
- trident hand
What is the cause of Wolf-Hirschhorn syndrome?
Chromosome abnormality: deletion of terminal 4p (which includes FGFR3)
What are the symptoms of Wolf-Hirschhorn syndrome?
- Growth deficiency
- Microcephaly
- Severe mental deficiency
- Hypertelorism (wide spaced eyes)
- Cleft lip/palate
- Micrognathia
What is the cause of achondroplasia?
- Gain of function mutation to FGFR3 (p.380G>R)
What is the normal function of FGFR3 and how is it abnormal in achondroplasia?
- Normal = fibroblast growth factor receptor; if FGF is bound there will be no bone growth
- Abnormal = acts as though ligand is bound => constitutive and unregulated inhibition of bone growth
Why do the symptoms of achrondroplasia not overlap with Wolf-Hirschhorn syndrome even though the same gene is affected?
- Achondroplasia = gain of function mutation
- Wolf-Hirschhorn = haploinsufficiency
