Clinical and biochemical features of naturally occurring α globin missense mutations analyzed in this study
| Mutation . | References . | Name . | Clinical features . | Predicted protein contacts . | ||||
|---|---|---|---|---|---|---|---|---|
| Mutated allele . | Percentage variant measured* . | Anemia . | Other features . | AHSP . | β globin (α1β1) . | |||
| R31S | 26-28 | Prato | α2 | 15-19 | Mild | Mild anisocytosis and hypochromia; variant Hb tetramer is mildly unstable in isopropanol | No | Yes |
| K99E | 25,41 | Turriff | α1, (α2)† | 10.5, 22 | No | Variant Hb tetramer comigrates with HbA1c; nascent chain is unstable in biosynthetic labeling studies (<5% total α globin) | Yes | No |
| K99N | 29 | Beziers | α1 | 15.8 | No | Comigrates with HbA1c | Yes | No |
| H103Y | 30 | Lombard | α2 | 8.4 | Mild | Yes | Yes | |
| H103R | 31 | Contaldo | ND | 20.4 | Moderate‡ | Microcytosis and hypochromia; Heinz bodies present α/β synthetic ratio 0.7, indicating possible concomitant α thalassemia in proband | Yes | Yes |
| F117S | 12 | Foggia | α2 | 0 | No | Mild microcytosis | Yes | Yes |
| P119S | 32-34 | Groene-Hart | α1 | 0 | Mild§ | Variant protein undetectable in hemolysate; microcytosis and hypochromia | Yes | Yes |
| A130D | 35 | Yuda | ND | 30 | None | Low oxygen affinity Hb | No | No |
| Mutation . | References . | Name . | Clinical features . | Predicted protein contacts . | ||||
|---|---|---|---|---|---|---|---|---|
| Mutated allele . | Percentage variant measured* . | Anemia . | Other features . | AHSP . | β globin (α1β1) . | |||
| R31S | 26-28 | Prato | α2 | 15-19 | Mild | Mild anisocytosis and hypochromia; variant Hb tetramer is mildly unstable in isopropanol | No | Yes |
| K99E | 25,41 | Turriff | α1, (α2)† | 10.5, 22 | No | Variant Hb tetramer comigrates with HbA1c; nascent chain is unstable in biosynthetic labeling studies (<5% total α globin) | Yes | No |
| K99N | 29 | Beziers | α1 | 15.8 | No | Comigrates with HbA1c | Yes | No |
| H103Y | 30 | Lombard | α2 | 8.4 | Mild | Yes | Yes | |
| H103R | 31 | Contaldo | ND | 20.4 | Moderate‡ | Microcytosis and hypochromia; Heinz bodies present α/β synthetic ratio 0.7, indicating possible concomitant α thalassemia in proband | Yes | Yes |
| F117S | 12 | Foggia | α2 | 0 | No | Mild microcytosis | Yes | Yes |
| P119S | 32-34 | Groene-Hart | α1 | 0 | Mild§ | Variant protein undetectable in hemolysate; microcytosis and hypochromia | Yes | Yes |
| A130D | 35 | Yuda | ND | 30 | None | Low oxygen affinity Hb | No | No |
Unless otherwise noted, all mutations were described in heterozygotes. R31S and A130D were used in this study as controls. Predicted protein contacts are derived from previously published structural data8 (and www.rcsb.org).
ND indicates not determined.
Values represent the percentage variant Hb tetramer (ααxββ) measured in circulation. For variants with normal production and protein stability, expected values are 44% to 46% for heterozygous α2 encoded alleles and 24% to 28% for heterozygous α1-encoded alleles (supplemental data). Values below these normal ranges suggest protein instability.
This mutation was presumed to occur in the α2 allele, given its relatively high expression.
Coexisting α thal-1 deletion.
Associated with variable mild anemia in the simple heterozygous state. Homozygous state associated with mild anemia. Heterozygosity appears to contribute to anemia when combined with deletional α thalassemia.