Table 1.
Hb variants that are discussed in this article
| Name | Globin site (fold) | Amino acid substitution | Molecular mechanism | Clinical phenotype | Other biochemical and laboratory findings |
|---|---|---|---|---|---|
| Unstable Mutants | |||||
| Brockton | β138 (H16) | Ala > Pro | Altered secondary structure | Hemolytic anemia, reticulocytosis | |
| Philly | β35 (C1) | Tyr > Phe | Altered α1β1 interface | Hemolytic anemia, reticulocytosis | Decreased cooperativity, increased oxygen affinity |
| Peterborough | β111 (G13) | Val > Phe | Altered α1β1 interface | Hemolytic anemia, reticulocytosis | Decreased oxygen affinity |
| Stanmore | β111 (G13) | Val > Ala | Altered α1β1 interface | Hemolytic anemia | Decreased oxygen affinity |
| J-Guantanamo | β128 (H6) | Ala > Asp | Altered α1β1 interface | Hemolytic anemia | Target cells |
| Khartoum | β124 (H2) | Pro > Arg | Altered α1β1 interface | Normal | |
| Prato | α1 or α2 31 (B12) | Arg > Ser | Altered α1β1 interface | Anisocytosis, hypochromia | Mildly unstable in isopropanol |
| Lombard | α2 103 (G10) | His > Tyr | Altered α1β1 interface | Anemia | |
| Contaldo | α1 or α2 103 (G10) | His > Arg | Altered α1β1 interface | Hemolytic anemia | |
| Foggia | α2 117 (GH5) | Phe > Ser | Altered α1β1 interface | Microcytosis | Rapidly degraded α chains |
| Groene Hart | α1 119 (H2) | Pro > Ser | Altered α1β1 interface, disrupted AHSP binding | Hemolytic anemia, microcytosis | |
| Turriff | α1 or α2 99 (G6) | Lys > Glu | Altered α1β1 interface, disrupted AHSP binding | Normal | Comigrates with HbA1C, rapidly degraded α chains |
| Beziers | α1 99 (G6) | Lys > Asn | Altered α1β1 interface, disrupted AHSP binding | Normal | Comigrates with HbA1C |
| Hirosaki | α2 43 (CE1) | Phe > Leu | Altered heme pocket | Heinz body hemolytic anemia | Hyperunstable |
| Terre Haute | β106 (G8) | Leu > Arg | Altered heme pocket | Heinz body hemolytic anemia, dominant inclusion body thalassemia | Hyperunstable |
| High Affinity Variants | |||||
| Kempsey | β99 (G1) | Asp > Asn | Unstable T state | Erythrocytosis | Decreased cooperativity |
| Hiroshima | β146 (HC3) | His > Asp | Mutated Bohr proton donor | Erythrocytosis | Decreased cooperativity, decreased Bohr effect |
| York | β146 (HC3) | His > Pro | Mutated Bohr proton donor | Erythrocytosis | Decreased cooperativity, decreased Bohr effect |
| Cowtown | β146 (HC3) | His > Leu | Mutated Bohr proton donor | Erythrocytosis | Decreased Bohr effect |
| Rahere | β82 (EF6) | Lys > Thr | Altered 2,3DPG binding site | Erythrocytosis | |
| Providence | β82 (EF6) | Lys > Asn | Altered 2,3DPG binding site | Erythrocytosis | Low oxygen affinity |
| Helsinki | β82 (EF6) | Lys > Met | Altered 2,3DPG binding site | Erythrocytosis | Decreased Bohr effect |
| Low Affinity Variants | |||||
| Kansas | β102 (G4) | Asn > Thr | Unstable R state | Cyanosis | Decreased cooperativity |
| Beth Israel | β102 (G4) | Asn > Ser | Unstable R state | Cyanosis | Decreased cooperativity |
| St. Mandé | β102 (G4) | Asn > Tyr | Unstable R state | Cyanosis | |
| Methemoglobin Variants | |||||
| M-Iwate | α1 or α2 (F8) | His > Tyr | Oxidized heme | Pseudocyanosis (Methemoglobinemia) | Abnormal visible spectrum |
| M-Saskatoon | β63 (E7) | His > Tyr | Oxidized heme | Pseudocyanosis (Methemoglobinemia) | Abnormal visible spectrum |
| Globin Chain Elongation Variants | |||||
| Constant Spring | α2 142 (HC3) | Stop > Gln | Antitermination mutant | Microcytosis | Decreased mRNA stability |
| Cranston | β145 (HC3) | +CT | Frameshift, elongated globin | Hemolytic anemia | Increased oxygen affinity, decreased cooperativity |
| Variants with Multiple Effects | |||||
| HbE | β26 (B8) | Glu > Lys | Unstable, reduced synthesis | Microcytosis | |
| Bruxelles | β41 (C7) or β42 (CD1) | Phe > 0 | Altered heme pocket | Hemolytic anemia, cyanosis, splenomegaly, reticulocytosis | Heinz bodies, decreased cooperativity |
| Warsaw | β42 (CD1) | Phe > Val | Altered heme pocket | Hemolytic anemia, cyanosis | Heinz bodies, decreased cooperativity |
| Hammersmith | β42 (CD1) | Phe > Ser | Altered heme pocket | Hemolytic anemia, cyanosis | Heinz bodies, decreased cooperativity |
| Buccuresti-Louisville | β42 (CD1) | Phe > Leu | Altered heme pocket | Hemolytic anemia, cyanosis | Heinz bodies, decreased cooperativity |
| Zurich | β63 (E7) | His > Arg | Altered heme pocket | Normal, but hypersensitive to oxidative stress | Decreased cooperativity, increased oxygen affinity, increased CO affinity |
| Jamaica Plain | β6 (A3) and β68 (E12) | Glu > Val and Leu > Phe | Altered secondary structure | Hemolytic anemia, cyanosis, splenomegaly, splenic sequestration | Unstable, Heinz bodies, sickle cell phenotype, decreased oxygen affinity |
| Quebec-Chori | β87 (F3) | Thr > Ile | Altered interaction with HbS polymer | Normal | Promotes HbS polymerization |
| D-Ibadan | β87 (F3) | Thr > Lys | Altered interaction with HbS polymer | Normal | Inhibits HbS polymerization |
| Bristol-Alesha | β67 (E11) | Val > Met | Altered heme pocket | Hemolytic anemia, reticulocytosis | Heinz bodies, decreased cooperativity, decreased Bohr effect, decreased oxygen affinity |
| Toms River | γ67 (E11) | Val > Met | Altered heme pocket | Anemia, cyanosis | Unstable, low oxygen affinity |
For a full listing of hemoglobin variants, see The Globin Gene Server (http://globin.bx.psu.edu; Hardison et al. 2002; Giardine et al. 2011).