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Biochem PULM > Hemoglobin Variants > Flashcards

Hemoglobin Variants Flashcards

1
Q

most Hb has what subunits?

A

a2B2

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2
Q

Hb can be composed of what polypeptides?

A

alpha, beta, gamma, delta

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3
Q

what chromosomes and gene clusters produce the polypeptides (chain) assembled into various hemoblogins?

A
  • chromosomes 11 and 16
    • chromosome 11
      • alpha like cluster –>
        • alpha chains
        • zeta chains
    • chromosome 16
      • beta like gene cluster –>
        • beta chains
        • gamma chains
        • delta chains
        • epsilon chains
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4
Q

discuss the Hb variants present throughout development, and what

  • poypeptides they consist of
  • genes those polypeptides came from
  • chromsomes those genes are on
A
  • embryonic = alpha, gamma, zeta and episilon polypeptides used.
    • zeta (from alpha cluster) and episilon (from beta cluster) are ONLY seen in embryonic.
    • combos:
      • zE (gower 1)
      • aE (gower 2)
      • portland (zy)
  • fetal = a2y2
  • adult = a2B2 > a2d2
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5
Q

the globin genes are activated in what direction along the chromosome? what effect does this have?

A

5’ –> 3’ direction.

  • polypeptides close to the 5’ end seen in earlier in life (zeta, episilon, gamma) and the 3’ end seen later in adulthood (beta, delta)
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6
Q

what leads to hereditary persistence of fetal Hb? what are the clinical imlications of this condition?

A
  • usually due to improper expression/deletion of the beta and delta globin genes, which are:
    • found closer to the 3’ of their chromosomes & normally expressed only in adulthood.
      • as a result, embryonic/ fetal chains (z, E, y) persist in the blood.
        • sustained levels of fetal Hb can be useful:
          • sickle cell
          • B-thalassemia
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7
Q

discuss the solubility of Hb & its significance

A
  • the Hb tetramer is highly soluble
  • however, individual subunits are not.
    • so, is subunits are not expressed in sufficient amounts/improperly assembled they can precipiate –> inclusions
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8
Q

discuss the primary, secondary, tertiary & quaternary strucutres of globins

A
  • primary: aa sequence - highly similar for each globin (polypeptide)
  • secondary: rich in alpha helices
  • tertiarty: hyrophobic aas in core, hydrophillic aas out
  • quaternary: two aB dimers (or other variation)
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9
Q

Hb quaternary structure is highly dependent on what interactions?

A
  1. proper hydrophobic/hydrophillic aa alignment
  2. a1b1 & a1B2 contant points
  3. His residue in F helix
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10
Q

how many amino acids are there?

A

20

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11
Q

what type of mutation causes sickle cell anemia (HbS)?

A

point mutation:

  • Glu –> Val in B subunit
    • this is a loss ot two negative charges:
      • Glu = -, hydrophillic
      • Val = neutral, hydrophobic
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12
Q

discuss the pathogenesis of sickle cell anemia

A
  • Glu –> Val mutation.
  • This Val residue is on the surface of the T-state (tense) molecule
  • Val residue interacts with other hydrophobic aas (phenylalinine, leucine) –> Hbs molecules aggregate
    • 14 HbS total HbS fiber
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13
Q

why is HbS aggregates less likely to form when HbS is oxygenated?

A
  • when oxygenated form, HbS is the in R-state.
    • the arrangement of aas shifts such that key hydrophobic residues (F, L) available to interact with mutant Val in the T-state become buried in the HbS core.
    • Val cannot make the non-polar bonds that lead to aggregation & HbS fiber formation.
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14
Q

how to dx sickle cell anemia?

A
  • by electrophoresis
    • due to structural HbS migrates differently than normal adult forms of HbA - a2B2, a2D2
      • the abnormal beta subunit (S)
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15
Q

heinz bodies

  • defintition
  • what forms them?
  • how are they detected?
  • clinical significance?
A
  • inclusions of denatured, aggregated Hb (typically Hb variants) within RBCs
  • clinical:
    • congenital heinz body hemolytic anemia (CHBA) - these RBCS are more susceptible to hemolysis
    • dx - smears stained for reticulocytes
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16
Q

discuss the clinical effects of high vs low affinity Hb variants

A
  • high affinity: decreased O2 delivery
    • asympomatic (m/c)
    • familial erthrocytosis
  • low affinity: normal O2 deliver, low O2 saturation
    • asymptomatic +/- cyanosis
17
Q

M hemoglobin

  • definition
  • clinical significance
A
  • Hb variation seen in methemoglobinema (ferric iron)
  • clinical presentation
    • asymptomatic, since patients has metHb reductase
      • lavendar blue skin, chocolate brown blood
18
Q

alpha thalassemia

  • cause/pathogenesis
  • clinical significance
A
  • cause/pathogenesis:
    • disruption of the all four alleles for alpha chain (chromosome 16)
    • a chain not made in suffcient quantity
      • HbH = 4 B-subunits
        • NO COOPERATIVITY
        • ​HIGH AFFINITY
  • clinical: poor oxygen release
19
Q

beta thalassemia

  • cause, pathogenesis
  • clinical significance
A
  • cause/pathogenesis
    • disruption of two alleles for Beta chain (chromsome 11)
    • only alpha chains produced
      • a subunits are insoluble –> precipitate in RBCs –> hemolysis –> Cooley anemia
20
Q

what is AHSP?

why is it important?

how does it work?

A
  • alpha-hemoblogin stabilizing protein
    • forms a soluble complex with newly synthesized, free alpha chain monomers preventing their aggregation/misfolding
      • ​binds both oxy & deoxy a-chain
        • the a-AHSP interface & aB interface in Hb is indentical
        • as B subunits are made, they displace ASHP
    • this is key since there are 4 a-chain alleles vs 2 B chain-alleles, & we need a way to manage excess a-subunits
21
Q

how does the structure of the alpha-chain change when it is bound to ASHP

A

this only applies to an oxygenated subunit:

  • the Fe2+ atom in that subunit ecomes bound to the distal histine rather than the proximal histidine
22
Q

ATXR

  • definition
  • inheritance pattern
  • clinical significance
A
  • alpha thalaessema X-inked intectual disability syndrome
  • X-linked recessive
  • characterized by intellectual disability & affects multiple organs
23
Q

what is HbH?

A
  • a hemoblogin variant made of only B-subunits (a homotetramer)
    • seen in alpha-thalasemmia
    • HbH = high oxygen affinity + no cooperativity = poor oxygen delivery
24
Q

HbCS mutation

  • cause/pathogenesis
  • clinical significance
  • treatment
A
  • mutation at the termination codon of the a2-globin gene
    • causes abnormally long alpha chains
  • clinical –> can lead to thallasemia intermedia
    • ​delayed growth
    • weak bones
    • enlarged sleen
  • tx - blood transufion
25
Q

thalasemia intermedia?

A
  • due to HBCS hemoglobin variant
    • mutation in a2 subunit, specically, which makes this alpha chain too long
      • –> growth defects: abrnomal bones, enlarged spleen

Biochem PULM (2 decks)

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