The normal human hbs at different stages of development Stage in Hb Structure Proportion in development normal adult Embryonic Gower I Gower l 08 2 Portland i 2y2 Fetal F <1 Adult A i2 97-98 00 2-3
The normal human Hbs at different stages of development Stage in development Hb Structure Proportion in normal adult (%) Embryonic Gower I Gower II Portland I ζ2 ε2 α2 ε2 ζ2γ2 - - - Fetal F α2γ2 <1 Adult A α2β2 97-98 α2δ2 2-3
02B2 22 282 A F A2 A Types of hemoglobin
Clinic disease: influences of gene Dosage and Developmental expression Dosage 4 a-VS 2 B-globin alleles per diploid genome Therefore mutations required in 4 a-globin alleles compared with 2 B-globin alleles for same 100% loss of function Ontogeny(个体发育) a expressed before vs. B expressed after birth Therefore, a-chain mutations have prenatal consequences, but B-chain mutations are not evidenced even in the immediate postnatal period
Clinic Disease: Influences of Gene Dosage and Developmental Expression • Dosage – 4 - vs. 2 -globin alleles per diploid genome – Therefore, mutations required in 4 -globin alleles compared with 2 -globin alleles for same 100% loss of function • Ontogeny（个体发育） – expressed before vs. expressed after birth – Therefore, -chain mutations have prenatal consequences, but -chain mutations are not evidenced even in the immediate postnatal period
Genetic disorders of hlb 1. Structural variant: alter the globin polypeptide without affecting its rate of synthesis 2. Thalassemia: reduced rate of production of one or more globin chains 3. Hereditary persistence offetal hemoglobin (HPFH.遗传性胎儿血红蛋白持续症):a group of clinically benign conditions, impairing the perinatal switch from y-to B-globin synthesis
Genetic disorders of Hb 1. Structural variant: alter the globin polypeptide without affecting its rate of synthesis 2. Thalassemia: reduced rate of production of one or more globin chains 3. Hereditary persistence of fetal hemoglobin (HPFH. 遗传性胎儿血红蛋白持续症) : a group of clinically benign conditions, impairing the perinatal switch from γ- to β-globin synthesis
There are >400 structural variants TABLE 11-3 The Major Classes of Hemoglobin Structural Variants Variant class* Amino Acid Substitution Pathophysiological Effect of Mutation Inheritance Hb s B chain: Glu6 Deoxygenated Hb S polymerizes→ sickle cells→ vascular AR occlusion and hemolySIs Hb Hammersmith B chain: Phe 42Ser An unstable hb→ Hb precipitation→ hemolysis;slso low oxygen affinit Hb Hyde park (a Hb m) B chain: His92Tyr The substitution makes oxidized heme iron resistant to AD methemoglobin reductase) Hb M, which cannot carry oxygen cvanosis asymptomatIc) Hb Kempsey B chain: Asp99Asn The substitution keeps the hb in its high oxygen affnity AD structure+ less oxygen to tissues polycythemia Hb e B chain: Glu26Lys The mutation> an abnormal Hb and decreased synthesis AR (abnormal RNA splicing)+ mild thalassemia(see
There are >400 structural variants