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a_Genetics > 11/19- Disorders of Connective Tissue- Skeletal > Flashcards

11/19- Disorders of Connective Tissue- Skeletal Flashcards

1
Q

Describe collagen biochemically

  • How many types
  • Mutations cause what
  • __ bound molecules
  • Where are precursor chains made
  • Other parts of production
A
  • Collagen bio-synthesis is complex
  • More than 16 different types, very abundant in connective tissue
  • Mutations in different collagen chains will lead to different diseases where those chains are mostly abundant
  • Triple bound molecules, individual precursor chains are synthesized in membrane bound polyribosomes
  • Hydroxylated and glycosylated in the rough endoplasmic reticulum (RER)
  • Transport, extrusion and proteolysis to remove carboxy (start) and amino (end) terminal propeptide extensions
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2
Q

What are the different types of collagen and where are they found?

  • Components
  • Diseases associated
A

Collagen type I is the one we’ll focus on

  • a1, a2, and a3
  • Found in skin, tendon, bone, and arteries
  • Associated with Osteogenesis Imperfecta

Other fun facts:

  • Collagen type 2: cartilage and vitreous humor
  • Collagen type 3: EDS type IV
  • Collagen type 4: found in basal lamina
  • Collagen type 5: EDS type I
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3
Q

Type I procollagen is made of what?

  • What chromosomes are involved
A
  • 2 pro-alpha 1 chains (chr 17)
  • 1 pro-alpha 2 chain (chr 7)
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4
Q

Describe the structure of type I procollagen

A
  • Triple helical structure arranged of tandem Gly-X-Y repeats
  • X = proline
  • Y = hydroxyproline or hydroxylysine
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5
Q

What is Osteogenesis Imperfecta

  • Inheritance pattern
  • Genes involved
  • Phenotypes
A

Disorders of collagen and collagen chaperon molecules (post-translation: hydroxylation).

  • Most common forms are autosomal dominant.
  • Rare recessive: CRTAP, FKBP10, LEPRE-1,PPIB, SERPINF1, SERPINH1, SP7.
  • Quantitative defects are associated with milder phenotypes while qualitative defects are more severe.
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6
Q

Describe the basics of OI type I

  • Incidence
  • Protein involved
  • Phenotype
A

Type I = mild form

  • 1/15-20,000
  • Type I collagen
  • Phenotype
  • Multiple recurrent fractures (common an ambulation; steady rate of fractures through childhood and then decrease after puberty; start up again after menopause in women and 60-80 yo in men)
  • Normal stature
  • Little or no bone deformity
  • Blue sclera
  • Hearing loss in 50%

- Quantitative defect

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7
Q

What are the type of mutations contributing to OI type I?

A

Pro-a1 null mutations

  • Haploinsufficiency of type I collagen (quantitative defect)
  • 1/2 the normal amount of normal type I collagen
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8
Q

What is seen here? What causes it?

A

Blue/grey sclera in OI type I

  • Due to thinning of sclera with color of vessels showing through
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9
Q

What is seen here?

A

Compression fractures

  • Bioconcave appearance of vertebrae (fish-shaped vertebrae)
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10
Q

Describe the severities of type II, III, and IV OI?

A

- Type II (fatal): lethal in the neonatal period

- Type III (deforming): severe and progressive deformity at birth

- Type IV: mild to moderate bone deformity and variable short stature, common dentinogenesis imperfecta (DI), variable sclerae, and hearing loss

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11
Q

As opposed to type I OI, types II-IV are ______ defects

A

As opposed to type I OI, types II-IV are qualtitative defects

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12
Q

Describe type II OI

  • Incidence
  • Gene mutation/consequences
  • Prognosis
  • Phenotype
A
  • Perinatal, lethal
  • Affects 1/20-60,000 (much rarer than type I)
  • Mutations in COL1A1
  • Glycine substitutions and mutations in the C-terminal pro-peptide (where the protein starts)
  • Phenotype: Minimal calvarial mineralization, beaded ribs, compressed femurs, long bones bowing, platyspondyly, small thoracic cage (pulmonary hypoplasia)
  • Ultimate cause of death is pulmonary hypoplasia
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13
Q

What is seen here?

A

OI type II (lethal)

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14
Q

Describe type III OI

  • Phenotype
A
  • Qualitative collagen defect.
  • Very short stature and bone deformities at birth due to in utero fractures.
  • Variable sclerae, dentinogenesis imperfecta (DI), hearing loss.
  • Recurrent fractures with minimal trauma + pain.
  • Severe deformities with ambulation restriction.
  • Adult height 3 ft - 4 ft.
  • Pulmonary insufficiency due to severe kyphoscoliosis.
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15
Q

What is seen here?

A

OI Type III (deforming type)

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16
Q

What is seen here?

A

OI type III (deforming type)

17
Q

Describe the stochiometric effect going on with Pro-a1 in OI types II, III, and IV

A
  • Decreased rate of triple helix formation
  • Increased post-translational modification of NH2 terminal to mutation
  • Decreased secretion and increased degradation
  • Defective collagen fibrils
  • Poor mineralization (in bone)
18
Q

Describe the stochiometric effect going on with Pro-a2 in OI types II, III, and IV

A
  • Biochemical abnormalities similar to the above (a1) but may be less severe
  • Phenotype depends on substitution
19
Q

Why are qualitative defects worse than quantitative?

A
  • Up to 75% of collagen molecules are abnormal
  • Abnormal trimers (greater severity than quantitative defects)
  • Exporting abnormalities = protein suicide (dominant negative)
20
Q

Which types of OI are AD?

A

All of them (I-IV)

21
Q

What types of mutations are more severe in OI?

A

“Subtle” point mutations (glycine substitutions) are more severe than large rearrangements which results in null alleles

  • Phenotypic gradient from carboxy-terminal to amino-terminal mutations
22
Q

____ have a ___ effect on normal collagen chains

A

Mutant collagen chains have a dominant negative effect on normal collagen chains

23
Q

Mutations in ___affect __% of collagen trimers while _____ mutations affect __% of the trimers

A

Mutations in COL1A1 affect 75% of collagen trimers while COL1A2 mutations affect 50% of the trimers

24
Q

What are treatments in OI?

  • Supportive
  • Interventional
A

Supportive

  • Orthopedic management: intramedullary rods, external braces, splints, castings
  • Hearing aids

Interventional

  • Infusion of biphosphonates: pamidronate (Aredia®), zoledronic acid (Zometa®)
25
Q

Describe the process of bone renewal and remodeling

  • Regulation
  • Effect of homones
A
  • Process that continues throughout life
  • Regulated by hormones and cytokines
  • Resorption of bone and deposition work in parallel (coupling)
  • Lower estrogen levels cause an increment in exchange with coupling dissociation => bone loss
26
Q

What is the basic mechanism behind bisphosphanate function?

A

Inhibit osteoclastic activity and induce apoptosis

27
Q

What are the 2 types of bisphosphanates?

A

- Pyrophosphate analogs: Clodronate, etidronate

- Nitrogen Analogs: Pamidronate, alendronate, risendronate, ibandronate, zoledronate

28
Q

Describe Pamidronate and Zoledronic acid

  • What type of bisphosphonate
  • Benefits
  • Side effects
A
  • Nitrogen analogs

Benefits:

  • Reduces pain caused by osteoporosis
  • Increases the bone density
  • Restores the shape integrity and height of the vertebral bodies

Side effects: osteonecrosis of the jaw (due to interference in angiogenesis)

29
Q

Describe the formation of skeletal elements (the developmental process and types of bone)

A

- Intramembranous ossification gives rise to the flat bones that comprise the cranium and medial clavicles

  • Ossification is accomplished directly.

- Endochondral ossification gives rise to long bones (appendicular skeleton, facial bones, vertebrae, and the lateral medial clavicles).

30
Q

What are the subtypes of micromelic (short) limbs?

A
  • Rhizomelic: short proximal limb
  • Mesomelic: short distal limb
  • Acromelic: short appendage (hand, foot)
31
Q

What are the most common skeletal dysplasias?

  • Prevalence
A
  • Thanatophoric dysplasia (1/10K)
  • Achondroplasia (1/20K)
  • Achondrogenesis (1/40K)
  • OI type II (1/60K)

Many more…

32
Q

Describe the genetics of Achondroplasia

  • Inheritance pattern
  • How many de novo
  • Associated with what
  • Gene/chromosome involved
  • Incidence
A
  • Autosomal dominant
  • 80% are new mutations
  • Advanced paternal age
  • Incidence 1/20,000
  • Gene mutated is FGFR3 located in 4p16.3
  • This is the most commonly mutate gene in humans (?)
  • 95% of cases change Glycine to Arginine in AA 380
33
Q

What are FGFRs?

  • Which is affected in achondroplasia
A

4 tyrosine kinase molecules that bind and are activated by most of the FGFs molecules (FGFR 1, 2, 3, and 4)

  • FGFR 3 is the one involved in Achondroplasia (ligands unknown)
34
Q

What happens when FGF ligands bind FGFR3?

A
  • Binding of FGF ligands to FGFR3 causes monomers to dimerize
  • Activates TK
  • Phosphorylation of tyrosine residues serve as docking sites for signaling molecules recruited for the receptor
  • MAP and STAT kinase signaling pathways relevant to inhibition of chondrocyte proliferation
35
Q

What happens to FGFR3 in Achondroplasia?

  • Consequences?
A
  • This mutation activates FGFR3 in the absence of ligand
  • Function: normal effect of signaling FGFR3 limits chondrocyte proliferation and differentiation within the epiphyseal growth plates and cause achondroplasia - Knockout FGFR3 mice have “longer” bones
  • FGFR3 appears to restrain and inhibit bone growth.

Achondroplasia appears to be the result of “a gain of function mutation” suggesting that receptor downregulates FGF signal transduction

36
Q

What are clinical features of Achondroplasia?

A
  • Macrocephaly, frontal bossing, midface hypoplasia
  • Short stature, rhizomelic shortening of the extremities
  • Trident hands
  • Short stature
  • Lumbar lordosis
  • Brachydactyly on exam and X-ray
37
Q

What is Thanatophoric Dysplasia?

  • Incidence
  • Genetics
  • Phenotype
A
  • “Thanatos”: death-seeking
  • Incidence: 1/10,000
  • Similar to homozgyous achondroplasia
  • Mutations in FGFR3:
  • IgII/III like domains for TD type I
  • TK domain in TD type II
  • Short femurs, flat vertebral bodies, short ribs
38
Q

What is the treatment for Thanatophoric Dysplasia?

A

- Conservative symptomatic management: suboccipital craniectomy for foramen magnum compression, spinal release, lower extremities osteotomies in case of bowing.

  • Experimental: Modified C-Natriuretic peptide (CNP)
39
Q

What is CNP? How does it work?

A

Modified C-Natriuretic peptide (CNP) used to treat Thanatophoric Dysplasia

  • CNP influences body fluid homeostasis and blood pressure control
  • CNP added to organ cultures of mouse tibias increases their length
  • Histological exams reveal the CNP increases the height and hypertrophic condrocyte zones in tibial epiphyses
  • CNP rescues achondroplasia phenotype in mice
  • CNP can rescue achondroplasia in achondroplasia mouse models and promotes long bone growth in normal monkeys
  • Current clinical trials (Phase II) are underway to assess modified CNP in a group of young children with achondroplasia

a_Genetics (18 decks)

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