【遗传学】第10章 生化遗传学.ppt

1. 引起溶血性贫血的Hb结构变异 HbC，第6位密码子单个碱基突变， 第二个被检测到的异常血红蛋白 大约2-3% 西非裔美国人Hb C杂合子 (单β链基因C突变)。血红蛋白C病(见于Hb C纯合子即双β链基因C突变)很少见且并不严重。通常引起少量贫血和轻微脾肿大。 HbS/HbC 复合杂合子 （Compound heterozygosity） 2.影响氧转运的Hb结构变异 高铁血红蛋白（methemoglobin） HbM A group of abnormal hemoglobins in which a single amino acid substitution favors the formation of methemoglobin and is thus associated with methemoglobinemia. Hb M Hyde Park β92His→Tyr Hb MBoston [α58His→Tyr] Hb MSaskatoon [β63His→Tyr] Hb MMilwaukee-1 [β67Val→Glu] 2.影响氧转运的Hb结构变异 Hb Kempsey is a β-chain variant in which Asp-β99 is replaced by Asn. In deoxy-Hb A, Asp-β99 normally forms an important hydrogen bond with Tyr-α42 at the α1β2 interface. Upon oxygenation, the two subunits shift in a dovetail fashion, so that the β99-α42 hydrogen bond is broken and another one forms between Asp-α94 and Asn-β102. In Hb Kempsey, substitution of Asp with Asn at β99 prevents formation of the former hydrogen bond with Tyr-α42 and therefore decreases stability of “deoxy” or T state structures. Thus, when this tetramer is fully deoxygenated, it remains partially in the R state. In contrast, Hb Kansas is a β-chain variant in which Asn-β102 is replaced by Thr. This position is also an important site at the α1β2 interface, which is involved in the transition between the oxy and deoxy conformation of hemoglobin. Hb Kansas has a low oxygen affinity because the hydrogen bond that usually occurs between Asn-β102 and Asp-α94 in normal Hb A, which functions to stabilize the oxy conformation, is absent, thus shifting the equilibrium toward the deoxy (T) conformation. 1995 The Journal of Biological Chemistry, 270, 26857-26862. 3.造成地中海贫血样表现的Hb结构变异 HbE An abnormal Hb with a single β chain substitution, molecular formula α2Aβ2 [26Glu→Lys], common in Southeast Asia, especially Thailand; heterozygotes are asymptomatic with 35-45% Hb E; homozygotes have mild to moderate hemolytic anemia with 90-100% Hb E and the remainder Hb F. 3.造成地中海贫血样表现的Hb结构变异 Hb Lepore an