Updated: 6/18/2021

Genetic Pearls

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  • Pediatric Dwarfisms
    • Autosomal Dominant
      Achondroplasia
      FGFR-3
      Inhibition of chondrocytes proliferation
      Apert Syndrome
      FGFR-2
      Inhibition of chondrocytes proliferation
      CMT (80-90%)
      PMP-22
      Nerve demyelination
      Pseudoachondroplasia
      COMP
      Abnormal cartilage formation
      SED congenita
      COL2A1 / Type II collagen
      Defect in cartilage matrix formation
      Kniest Dysplasia
      Type II collagen
      Type II collagen
      MED - Type I
      COMP
      Type II collagen
      MED - Type II
      Type IX collagen
      Type IX collagen
      Jansen's metaphyseal chondrodysplasia
      PTHrP
      Functional defect in parathyroid hormone
      Schmid's metaphyseal chondrodysplasia
      Type X Collagen
      Defect in cartilage matrix formation
      Cleidocranial dysplasia
      RUNX2/CBFA1
      Impaired intramembranous ossification
      Osteogenesis Imperfecta
      (Type I, IV)
      COL1A1/COL1A2
      Type I collagen
    • Autosomal Recessive 
      Diastophic dysplasia
      DTD 
      (Sulfate Transport Protein)
      Defect in sulfaction of proteoglycan
      Friedreich's Ataxia
      Frataxin
      Osteogenesis Imperfecta
      (Type II, III)
      COL1A1/COL1A2
      Type I collagen
      McKusick metaphyseal
      Unknown
    • X-Linked Recessive
      SED tarda
      COL2A1
      Type II collagen
      CMT (10-20%)
      Connexin gene
      Nerve demyelination
  • Epigenetics
    • Overview
      • epigenetic changes include inheritable genetic alteration (developmental or environmental cues) that do NOT involve DNA mutation
      • DNA methylation, histone modification, nucleosome location, or noncoding RNA are components of epigenetics
      • osteoarthritis is thought to have epigenetic mechanisms that influence the disease process
  • Translocations
    • Overview
      • translocations allow expression of genes (oncogenes) that are usually not active.
      • cytogenetic analysis allows for the detection of gene translocations by evaluating the size and number of chromosomes isolated from the cell nucleus.
    • Examples
      • present in up to 95% of sarcomas.
      • Translocations
        Disease
        Translocation
        Gene
        Ewing's sarcoma
        t (11:22)
        Fusion protein (EWS-FLI1)
        Rhabdomyosarcoma
        t (2:13)
        Pax3-FKHR
        Myxoid liposarcoma
        t (12:16)
        TLS-CHOP
        Synovial sarcoma
        t (X:18)
        SYT-SSX1, 2, or 4 fusion protein
        Clear cell sarcoma
        t (12:22)
        Fusion protein EWS-ATF1
        Chondrosarcoma
        (Myxoid Variant)
        t (9:22)
        Fusion protein EWS-CHN
  • Tumor Suppressor Genes
    • Definition
      • inhibit cell proliferation
      • therefore a mutation interfering with normal function causes leads to uncontrolled cell growth
    • Examples
      • retinoblastoma protein (pRB-1)
        • acts as a regulator of gene expression
        • recessive suppressor
          • both alleles must be mutated to have uncontrolled growth
        • Rb mutation in
          • 100% of retinoblastomas
          • 35% of osteosarcomas
        • abnormal state is phosphorylated and unable to bind to DNA to regulate
      • p53
        • normal protein prevents entrance into S-phase of cell cycle when DNA is damaged
        • dominant suppressor
          • single allele must be mutated to have uncontrolled growth
        • mutation in this gene found in
          • 50% of all tumors
          • osteosarcoma (20-65%)
          • chondrosarcoma
          • Li-Fraumeni syndrome
  • Oncogenes
    • Definition
      • induce uncontrolled growth
      • normal function causes leads to uncontrolled cell
    • Examples
      • FAK
        • focal adhesion kinase)
      • Erb-2
        • epidermal growth factor variant
  • Tumor Antigens
    • Definition
      • tumor antigens are used in the diagnosis, monitoring of treatment response, and are being researched for treatment options as anti-cancer vaccines
    • Examples
      • carcinoembryonic antigen (CEA)
        • colorectal carcinoma
      • carbohydrate antigen 19-9 (CA-19-9)
        • pancreatic cancer
      • carbohydrate antigen 125 (CA-125)
        • ovarian cancer
      • cancer antigen 15-3 (CA-15-3)
        • breast cancer
      • alpha fetoprotein (AFP)
        • can be seen in many cancers, but is most commonly seen in hepatocellular carcinomas
  • Assays
    • Western blot
      • detects protein
    • Southern blot
      • detects DNA
    • Northern blot
      • detects RNA
    • Southwestern blot
      • detects DNA binding proteins
    • RT-PCR
      • reverse transcription PCR
      • highly sensitive, detects low copy number of RNA
      • reversed transcribed into complimentary DNA (cDNA)
      • may be used together with Northern blot
    • siRNA
      • small interfering RNA; blocks translation of mRNA
      • useful for loss-of-function experiment designs

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(OBQ12.165) DNA methylation, histone modification, nucleosome location, or noncoding RNA are hypothesized to contribute to the process whereby inheritable genetic alterations occur that do not involve DNA mutation. Which of the following terms best defines this process?

QID: 4525
1

Transgenes

7%

(278/4225)

2

Epigenetics

63%

(2655/4225)

3

Gene enhancers

7%

(278/4225)

4

Gene promoters

7%

(294/4225)

5

Transformation

16%

(670/4225)

L 4 D

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(OBQ08.156) Which of the following laboratory tools is used to detect genetic translocations for prenatal screening?

QID: 542
1

Western blot analysis

5%

(61/1220)

2

Northern blot analysis

4%

(45/1220)

3

Enzyme linked immunosorbent assay (ELISA)

13%

(161/1220)

4

Cytogenetic analysis

75%

(913/1220)

5

Flow cytometry

3%

(35/1220)

L 2 D

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(OBQ07.266) Which of the following chromosomal translocations is associated with osteosarcoma?

QID: 927
1

SYT-SSX1

9%

(63/701)

2

CHOP-TLS

8%

(59/701)

3

EWS-FLI1

11%

(74/701)

4

FKHR-PAX3

8%

(53/701)

5

no translocation associated

64%

(450/701)

L 2 D

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(OBQ07.82) What serum marker is most closely associated with colorectal carcinoma?

QID: 743
1

Carbohydrate antigen 125

14%

(223/1632)

2

Carcinoembryonic antigen

78%

(1265/1632)

3

Carbohydrate antigen 19-9

5%

(83/1632)

4

Cancer Antigen 15-3

1%

(16/1632)

5

Alpha fetoprotein

3%

(41/1632)

L 2 D

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(OBQ06.95) A mutation of the retinoblastoma gene RB-1 leads to the development of malignancies such as retinoblastoma and osteosarcoma. Which term best characterizes the RB-1 gene?

QID: 206
1

growth factor

0%

(3/628)

2

retro-oncogene

1%

(7/628)

3

proto-oncogene

18%

(110/628)

4

oncogene

11%

(72/628)

5

tumor suppressor

69%

(433/628)

L 3 D

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(OBQ04.268) Which of the following sarcomas is correctly paired with its most common translocation?

QID: 1373
1

Alveolar rhabdomyosarcoma: t(9;22)

18%

(323/1791)

2

Synovial sarcoma: t(11;22)

8%

(135/1791)

3

Ewing's sarcoma: t(12;16)

5%

(93/1791)

4

Myxoid liposarcoma: t(X;18)

10%

(176/1791)

5

Clear cell sarcoma t(12;22)

59%

(1053/1791)

L 3 D

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