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Foundations 1 > Autosomal Dominant Disorders > Flashcards

Autosomal Dominant Disorders Flashcards

1
Q

In what ways can dominant mutations cause disease?

A
  • Loss of function: haploinsufficiency and dominant negative

- Gain of function

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2
Q

Haploinsufficiency

A
  • Cause of autosomal dominant disease

- When a half dosage of a normal gene product is insufficient for normal functionality

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3
Q

Dominant negative

A
  • Cause of autosomal dominant disease

- When the half dosage of abnormal gene product causes MORE than half reduction in functionality

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4
Q

What kind of disorder is familial hypercholesterolemia?

A
  • Autosomal dominant caused by haploinsufficiency
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5
Q

What is the cause of familial hypercholesterolemia?

A
  • Insufficient LDL receptors (haploinsufficiency)
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6
Q

What are symptoms of familial hypercholesterolemia?

A
  • Fatty deposits in skin and blood vessels => life expectancy < 20
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7
Q

What kind of disorder is caused by insulin Chicago?

A

Dominant negative: heterozygotes get diabetes

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8
Q

Describe the mutation and altered functionality of insulin Chicago.

A
  • Phe>Leu near B-chain C-ter

- Binds to insulin receptors (preventing normal insulin binding) but does not promote glucose uptake

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9
Q

How can a mutation to a subunit of a protein dimer have a dominant negative effect?

A
  • 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
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10
Q

Collagen

A
  • Extracellular proteins that are a component of connective tissue
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11
Q

How is collagen synthesized?

A
  • 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
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12
Q

What is the mechanism of osteogenesis imperfecta?

A

Protein suicide (dominant negative)

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13
Q

How can a mutant collagen alpha-1 allele cause protein suicide?

A
  • 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
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14
Q

Why does osteogenesis imperfect have variable clinical severity?

A
  • 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
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15
Q

What are symptoms of osteogenesis imperfecta?

A
  • frequent fractures

- blue sclera

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16
Q

What are the symptoms of Ehlers-Danlos syndrome?

A
  • 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
17
Q

What is the mechanism of EDS?

A
  • haploinsufficiency of type 5 collagen
18
Q

What mutations cause EDS?

A

type 5 collagen mutations generating a null allele

19
Q

What are the symptoms of achondroplasia?

A
  • Small stature
  • disproportionate shortening of proximal limb segments
  • short skull base with large head
  • spinal stenosis
  • normal intelligence
  • accentuated lumbar lordosis
  • trident hand
20
Q

What is the cause of Wolf-Hirschhorn syndrome?

A

Chromosome abnormality: deletion of terminal 4p (which includes FGFR3)

21
Q

What are the symptoms of Wolf-Hirschhorn syndrome?

A
  • Growth deficiency
  • Microcephaly
  • Severe mental deficiency
  • Hypertelorism (wide spaced eyes)
  • Cleft lip/palate
  • Micrognathia
22
Q

What is the cause of achondroplasia?

A
  • Gain of function mutation to FGFR3 (p.380G>R)
23
Q

What is the normal function of FGFR3 and how is it abnormal in achondroplasia?

A
  • 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
24
Q

Why do the symptoms of achrondroplasia not overlap with Wolf-Hirschhorn syndrome even though the same gene is affected?

A
  • Achondroplasia = gain of function mutation

- Wolf-Hirschhorn = haploinsufficiency

25
Q

What is the pattern of transmission of familial male precocious puberty?

A

Autosomal dominant X-linked

26
Q

What is the cause of familial male precocious puberty?

A

Gain of function mutation to LH receptor

27
Q

What is the normal function of the LH receptor and how is it abnormal in familial male precocious puberty?

A

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

Foundations 1 (26 decks)

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