TABLE 28-5 (
Very low 0
Unstable; increases 0
Also called D-Punjab; benign; enhances sickling in
heterozygotes with HbS.
As for HbD-LosAngeles.
Unstable; mild hemolysis; normal 0
affinity, decreases Bohr effect; loss of
positive group at DPG binding site.
Decreases DPG binding and Bohr effect; increases
affinity; deletes C-terminal residues;
eliminates C-terminal bonding.
affinity; decreases Bohr effect and
DPG binding; disrupts C-terminal H bond,
Mutations Causing Congenital Methemoglobinemia
Only known in heterozygotes; all cause a benign
*The first number is the residue position, with 1
being the N-terminal amino acid; Kendrew’s helical notation is given in parentheses.
+Codon assignments are based on published sequences for human a- and p-globin genes. Sequences of the alpha-1 and alpha-2 globin genes do not
differ from each other at any of the codons used above. In a few instances, the normal codon could have mutated to either of two or three codons; these
ambiguities are indicated by: term = termination codon; — means codon (and amino acid) deleted. The codons shown here would occur on the
nontranscribed strand in DNA.
t Benign means no observable symptoms.
affinity. In hemoglobins Yoshizuka, Presbyterian, and
Peterborough, the «i/J,
interface also is affected, but
they exhibit decreased oxygen affinity because the R-state
(oxyhemoglobin) is more destabilized than the T-state.
Contacts at the
interface stabilize the interaction
of the two
dimers through the packing contacts and
allow subunit motion during the
the sliding contacts. Mutations in the
chains of Hb
Kansas and Hb Beth Israel at this interface eliminate a
hydrogen bond found only in the R-state, destabilizing the
R-state and decreasing oxygen affinity and dissociation of
the tetramer. The oxygen affinities of these variants are so
low that they cause cyanosis, usually seen only in methe-
moglobinemia. Hb Chesapeake has an a-chain mutation
that affects the
interface, stabilizing the R-state and
increasing oxygen affinity. Otherai/3
such as HbG Georgia, dissociate into dimers upon oxy-
genation and reassociate to tetramers when oxygen is re-
The deleterious effect of an amino acid substitution
is due to replacement of a useful side chain by one that
cannot perform the necessary function. The importance of
a side chain may reside in its size, shape, or charge. A side
chain that is too small (Hbs Torino, Hammersmith, and
Sydney) or too large (Hbs Savannah and Peterborough)
can be disruptive. Because 80% of the globin chain has
a helical conformation, mutations that introduce proline
residues are likely to disrupt this structure because proline