浙江大学医学院：血红蛋白病的遗传学和新生儿血红蛋白筛查 Genetics of the Hemoglobinopathies & Newborn Screening for the Hemoglobinopathies

Genetics of the Hemoglobinopathies & Newborn Screening for the Hemoglobinopathies 张咸宁 zhangxianning@zju.edu.cn Tel:13105819271;88208367 Office: A705, Research Building 2013/03

Genetics of the Hemoglobinopathies & Newborn Screening for the Hemoglobinopathies 张咸宁 zhangxianning@zju.edu.cn Tel：13105819271; 88208367 Office: A705, Research Building 2013/03

Required Reading Thompson &Thompson Genetics in Medicine,7Ed(双语版,2009) ● Pages237-257 O Clinical Case Studies: 37. Sickle Cell Disease 39. Thalassemia

Required Reading Thompson &Thompson Genetics in Medicine, 7th Ed （双语版，2009） ● Pages 237-257; ● Clinical Case Studies: 37. Sickle Cell Disease 39. Thalassemia

Part i genetics of the Hemoglobinopathies

Part I. Genetics of the Hemoglobinopathies

Learning obiectives 1. To review the normal structure-function relationships of hemoglobin and expression of globin genes 2. To examine the hemoglobinopathies as disorders of hemoglobin structure. or a or B-globin gene expression 3. To explore the influences of compound heterozygosity and modifier genes on hemoglobinopathy phenotypes

Learning Objectives 1. To review the normal structure-function relationships of hemoglobin and expression of globin genes 2. To examine the hemoglobinopathies as disorders of hemoglobin structure, or α- or β-globin gene expression 3. To explore the influences of compound heterozygosity and modifier genes on hemoglobinopathy phenotypes

Molecular disease a disease in which there is an abnormality in or a deficiency of a particular molecule, such as hemoglobin in sickle cell anemia

Molecular Disease A disease in which there is an abnormality in or a deficiency of a particular molecule, such as hemoglobin in sickle cell anemia

The effect of mutation on pr function 1. Loss of Pr function(the great majority is seen in (Recessive diseases; (2)diseases involving haploinsufficiency, in which 50%of the gene product is insufficient for normal function; and 3)dominant negative mutations, in which the abnormal protein product interferes with the normal protein product

The Effect of Mutation on Pr Function 1. Loss of Pr function (the great majority): is seen in (1)recessive diseases;(2)diseases involving haploinsufficiency, in which 50% of the gene product is insufficient for normal function; and (3)dominant negative mutations, in which the abnormal protein product interferes with the normal protein product

The effect of mutation on pr function 2. Gain of function are sometimes seen in dominant diseases 3. Novel property (infrequent) 4. The expression of a gene at the wrong time (Heterochronic expression), or in the wrong place(Ectopic expression), or both. (uncommon, except in cancer)

The Effect of Mutation on Pr Function 2. Gain of function: are sometimes seen in dominant diseases. 3. Novel property (infrequent) 4. The expression of a gene at the wrong time (Heterochronic expression), or in the wrong place (Ectopic expression), or both. (uncommon, except in cancer)

MUTATION Mutations in Mutations disrupting Mutations affecting coding region RNA stability gene regulation or dosage RNA splicing Protein abnormal Protein structure normal Decreased Hb Hammersmith (if unstable ->decreased amount) amount CAUSE OF DISEASE aE-thalassemias B-thalassemias Monosomies Increased Tumor-suppressor mutations Loss of protein function amount Hb Kempsey Achondroplasia the great majority) Trisomies Charcot- Marie- Tooth Gain of function disease type 1A HPFH Novel property Many oncogenes (infrequent Inappropriate expression (wrong time, place Ectopic or heterochronic expression (uncommon, except in cancer @ElsevierNussbaumetal:ThompsonandThompsonsGeneticsinMedicine7e-www.studentconsult.com

Hemoglobinopathies Disorders of the human hemoglobins Most common single gene disorders in the world WHO: 5% of the worlds population are carriers for clinically significant hemoglobinopathies Well understood at biochemical and molecular levels

Hemoglobinopathies • Disorders of the human hemoglobins • Most common single gene disorders in the world – WHO: 5% of the world’s population are carriers for clinically significant hemoglobinopatihies • Well understood at biochemical and molecular levels

HbA: a2B2 Globular tetramer MW645KD a-Chain Maps to chromosome 16 Polypeptide length of 141 amino acids 阝 Chain Maps to chromosome 11 Polypeptide length of 146 amino acids

HbA: α2β2 • Globular tetramer • MW 64.5 kD • α-Chain – Maps to chromosome 16 – Polypeptide length of 141 amino acids • β-Chain – Maps to chromosome 11 – Polypeptide length of 146 amino acids