666
CHAPTER 28
Hemoglobin
TABLE 28-5 (
Continued
)
Hemoglobin
Position*
Amino Acid
Change
DNA Codon1
Alterations
Remarks*
Kansas
102(G4)
Asn—»Thr
AAC-aACC ]_
Very low 0
2
affinity; cyanosis.
Beth Israel
102(G4)
Asn—»Ser
AAC—»AGC j
Yoshizuka
108(G10)
Asn—»Asp
AAC-aGAC
Presbyterian
108(G10)
Asn—»Lys
AAC-»AA(A,G) 1
Unstable; increases 0
2
affinity;
a1f5
l-contact
San Diego
109(G11)
Val—»Met
GTG-»ATG
|
mutant
Peterborough
111(G13)
Val—»Phe
GTC—»TTC
Indianapolis
112(G14)
Cys^Arg
TGT—»CGT
Unstable.
D-Los Angeles
121(GH4)
Glu—»Gin
GAA-»CAA
Also called D-Punjab; benign; enhances sickling in
heterozygotes with HbS.
O-Arab
121(GH4)
Glu—»Lys
GAA—»AAA
As for HbD-LosAngeles.
North Shore
134(H 12)
Val—»Glu
GTG—»GAG
Unstable; mild hemolysis; normal 0
2
affinity.
Syracuse
143(H21)
His —»Pro
CAC—»CCC
Increases 0
2
affinity, decreases Bohr effect; loss of
positive group at DPG binding site.
McKees Rocks
145(HC2)
Tyr—»term.
TAT-^TAA
Decreases DPG binding and Bohr effect; increases
0
2
affinity; deletes C-terminal residues;
eliminates C-terminal bonding.
Bethesda
1145(HC2) Tyr—»His
TAT-^CAT
__
Increases 0
2
affinity; decreases Bohr effect and
Cowtown
146(HC3)
His —»Leu
CAC—»CTC
DPG binding; disrupts C-terminal H bond,
destabilizes T-state.
Mutations Causing Congenital Methemoglobinemia
«-Chain:
M-Boston
58(E7)
His—»Tyr
CAC—»TAC
M-Iwate
/3-Chain:
87(F8)
His—»Tyr
CAC-^TAC
Only known in heterozygotes; all cause a benign
M-Freiburg
23(B5)
Val—»—
GTT—»—
*
cyanosis.
M-Saskatoon
63(E7)
His—»Tyr
CAT-»TAT
M-Milwaukee
67(E11)
Val-»Glu
GTG-^GAG
M-Hyde Park
92(F8)
His—»Tyr
CAC—»TAC
J
*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
a\p2
interface stabilize the interaction
of the two
a/3
dimers through the packing contacts and
allow subunit motion during the
transformation at
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
a\P2
interface, stabilizing the R-state and
increasing oxygen affinity. Otherai/3
2
interface mutants,
such as HbG Georgia, dissociate into dimers upon oxy-
genation and reassociate to tetramers when oxygen is re-
moved.
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
