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

Genetics of the hemoglobinopathies Newborn Screening for the Hemoglobinopathies 张成宁 zhangxianning@zju.edu.cn Tel:13105819271:88208367 Office: C303, Teaching Building 2016/03

Genetics of the Hemoglobinopathies & Newborn Screening for the Hemoglobinopathies 张咸宁 zhangxianning@zju.edu.cn Tel：13105819271; 88208367 Office: C303, Teaching Building 2016/03

Required Reading Nussbaum RL, et al. thompson Thompson Genetics in Medicine, 8th ed Elsevier, 2016, pp195-214 O Clinical case Studies-42. Sickle Cell Disease, 44. thalassemia

Required Reading Nussbaum RL, et al. Thompson & Thompson Genetics in Medicine, 8th ed. Elsevier，2016，pp195-214； ● Clinical Case Studies-42. Sickle Cell Disease，44. Thalassemia

Part i。 Genetics of the Hemoglobinopathies血红蛋白病

Part I. Genetics of the Hemoglobinopathies血红蛋白病

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

Compound heterozygote(复合杂合子) An individual, or a genotype, with two different mutant alleles at the same locus · Compound heterozygote≠ homozygote≠ Double heterozygote

• Compound heterozygote（复合杂合子）： An individual, or a genotype, with two different mutant alleles at the same locus • Compound heterozygote ≠ homozygote ≠ Double heterozygote

Molecular disease(分子病) a disease in which there is an abnormality in or a deficiency of a particular molecule, such as hemoglobin in sickle cell anemia 酶蛋白病( enzymopathy): Any of a group of congenital disorders caused by an inherited defect in a single specific enzyme that results in a disruption or abnormality in a specific metabolic pathway

Molecular Disease（分子病） A disease in which there is an abnormality in or a deficiency of a particular molecule, such as hemoglobin in sickle cell anemia 酶蛋白病（enzymopathy）：Any of a group of congenital disorders caused by an inherited defect in a single specific enzyme that results in a disruption or abnormality in a specific metabolic pathway

Hemoglobinopathies血红蛋白病 Disorders of the human hemoglobins The 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血红蛋白病 • Disorders of the human hemoglobins • The 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/HbF: a2Y2 Globular tetramer MW645KD a-Chain 16pl33 Polypeptide length of 141 amino acids 阝 Chain 11p15.4 Polypeptide length of 146 amino acids

HbA: α2β2 / HbF: α2 γ2 • Globular tetramer • MW 64.5 kD • α-Chain – 16p13.3 – Polypeptide length of 141 amino acids • β-Chain – 11p15.4 – Polypeptide length of 146 amino acids

Globin Tertiary structure Myoglobin One O2 binding site 阝 Hemoglobin A Four O2 binding sites

Globin Tertiary Structure

BLCR YG YA YB1 8 B TH IHm Chromosome 11: B-globin genes Hs-40 yC2 vC1 yo2 vol a2 a1 01 I IH HH HIHI Pseudogene 0 10 20 30 50 60 kb Chromosome 16: a-globin genes Gene cluster基因簇: a group of adjacent genes that are identical or related Pseudogene假基因: DNA Sequence homologous with a known gene but is non-functional

Gene cluster基因簇: A group of adjacent genes that are identical or related Pseudogene假基因: DNA sequence homologous with a known gene but is non-functional