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
What is the pattern of transmission of familial male precocious puberty?
Autosomal dominant X-linked
What is the cause of familial male precocious puberty?
Gain of function mutation to LH receptor
What is the normal function of the LH receptor and how is it abnormal in familial male precocious puberty?
Normal: LH binds to GPCR => conformational change inside the cell => ATP binds and generates cAMP => testosterone production
Abnormal: ATP can bind un-ligand-bound GPCR => constitutive generation of cAMP
