Study On Molecular Diagnostics,Gene Defects And Epidemology Of α-Thalassemia

ABSTRACT Study on Molecular Diagnostics, Gene Defects and Epidemiology of ct-Thalassemia Ph.D. candidate: Yongzhong ZHAO Superviser: Prof. Xiangmin XU a-thalassemia (a-thai), which characterized by the imbalance of a-globin chain and 13-globin chain due to absent or decreased a-globin synthesis, is one of the most common genetic disease, and widely spread in Mediterranean country, South East Asia, south China, India and north Africa. Generally, alpha-thais are mainly caused by a-giobin gene defects. a-giobin genes lie in a-globin gene cluster, which is located in 16pI3.3, containing 2 a-globin genes (cc2, 0M1M141850, HBA2; al, 0M1M141800, HBA 1), 1 embryonic a-like gene (~2, OMIM 14231 O,HBZ),3 pseudo-genes(~l, ~jJa2, ~ai) and functional unknown gene ( 01, 0M1M14220,HBQ1 ) , all of which are arranged as 5?-~2-~j4 1 -~a2-~a I -a2-a 1-01-3? The main features of a-globin gene cluster include high G+C contents, much homology and similarity among these genes, etc. Gene deletions and point mutations of a-globin gene are the main molecular defects of a-thai. Definitely, deletion of both two a-globin genes in cis is called deletionai ct0-thal, whereas deletion of either globin gene is called deletional a~-thal. In addition, point mutation or a few nucieotides deletion can also cause a-thai, which is designated as non-deletion a~-thal. To date, at least 43 types of deletional a-thai and 46 types of non-deletion a-thai have been reported throughout the world population. In China, four types ~ THA1 and ....HW) three types a~-thal(-&7,-a42 and-a27) and 5 types non-deletional a-thal(aa~~, CD3O wS CD59 aa , aa and aa ) have been identified. a-thai could be classified into four groups, a-thai silent, a-thai trait, Hb H disease, and Hb Bait抯 Hydrops Fetaiis according to its clinical -8- H disease, and Hb Bart抯 Hydrops Fetalis according to its clinical manifestation. Although molecular defects of these four kinds of o-thai might be overlapping, generally they are different. a-thal silent, with a hardly distinguished hematological feature, usually results from the interaction of a normal allele and an cC-thai determinants. Clinically, it is almost impossible to diagnose a-thai traits because of the absence of abnormal red blood cells parameters, such as, low MCV, low MCH, low Hb concentration and a reduced a-chain synthesis with a/13 ratio within the range 1.1-1.4. a-thaI traits are mainly caused by interaction of a normal allele and an a0-thal determinants, as well as homozygosity or compound heterozygosity for cC-thai determinants. The HbH disease syndrome, also called a-thal intermedia, characterized by a much variable clinical condition, is originated from the interaction of cC and a0-thal determinants . Features typical for Hb H disease are the presence of variable amount of Hb H (0.8-40%) , anemia, jaundice, and obvious splenomegaly with hypersplenism. Hb Bart抯 Hydrops Fetalis Syndrome, the most severe form of a-thalassemia, always results T SEA from the complete absence (--I--) or extreme low level(aa I-- ) of a-globin synthesis. Currently, antenatal diagnosis and selective abortion is the first choice to control...