Biology of Disease

Hemoglobin Codon change Amino acid

changed

Comments

Torino TTC to GTC Phe to Val A-chain (43); decreased O 2 affinity,

unstable

Ann Arbor CTG to CGG Leu to Arg A-chain (80); unstable

Bibba CTG to CCG Leu to Pro A-chain (136); dissociates

M-Iwate CAC to TAC His to Tyr A-chain (87); forms met-Hb,

benign cyanosis in heterozygotes

Constant Spring UAA to CAA STOP to Gln A-chain mutation of the chain

termination codon (142) gives

extendedA-chain

S GAG to GTG Glu to Val B-chain (6); cells sickle, forms fibrils

C GAG to AAG Glu to Lys B-chain (6); enhances sickling when

with HbS

St Louis CTG to CAG Leu to Gln B-chain (28); Fe readily oxidized, polar

group in heme pocket, increased O 2

affinity, unstable

Seattle GCC to GAC Ala to Asp B-chain (70); decreased O 2 affinity,

unstable

Gun Hill – deletion B-chain (91-95); increased O 2 affinity,

unstable

M-Saskatoon CAT to TAT His to Tyr B-chain (63); forms met-Hb, benign

cyanosis in heterozygotes

Table 13.2Some of the many know mutations in hemoglobin genes

Embryonic and Fetal Hemoglobins

The embryonic and the fetal forms of Hb differ slightly from HbA. There are
several types of embryonic Hb present early in embryonic life but at about
6 weeks there is a switch to fetal Hb (HbF). Fetal Hb has two A subunits, as
in the adult, but two G subunits, (A 2 G2, and there are actually two types of G
subunit). The embryo and fetus obtain their oxygen from the mother’s blood
in the placenta. Thus their Hbs need to become saturated with oxygen at lower
oxygen tensions than maternal HbA so they can obtain it from the mother
(Figure 13.8). This is possible because embryonic and fetal Hbs have a greater
affinity for O 2 than HbA. Adult Hb production starts shortly before birth and
by 30 weeks of age it should have replaced all the HbF (Figure 13.9).

HEMOGLOBINS

CZhhVg6]bZY!BVjgZZc9Vlhdc!8]g^hHb^i]:YLddY (*&

50

40

30

20

10

Proportion

of total

globin

synthesis / %

Postconceptual

age / weeks

Postnatal

age / weeks

Birth

6 121824 30361 6 121824 30 36 42













Embryonic

Fetal

Adult

Adult

Maternal

hemoglobin

Fetal

hemoglobin

Saturation of hemoglobin with oxygen / %

100

75

50

25

0

04 81216

Oxygen tension / kPa

Partial pressure of oxygen / mmHg

0 25 50 75 100

Figure 13.8 Graph showing that fetal

hemoglobin has a higher affinity for oxygen than

adult, maternal hemoglobin. This allows the fetus

to obtain oxygen from the maternal blood.

Figure 13.9 The production of human globins

during development. There are several types of

B-globins in the embryo and the fetus. Any given

erythrocyte contains only one type of A- and one

type of B-globin.

Margin Note 13.3 Hereditary

persistence of fetal hemoglobin

Inhereditary persistence of fetal

hemoglobin (HPFH), the HbF is not

replaced. This is presumably due to

a failure of the switching mechanism

that normally occurs at around the

time of birth. Although individuals

with HPFH have high concentrations

of HbF, the condition does not

cause any major hematological

abnormalities and does not prevent

those affected from having a normal

life.

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