Molecular Genetics of Sideroblastic Anemia

铁粒幼细胞贫血的分子遗传学

• 批准号: 8460926
• 负责人: MARK D FLEMING
• 金额: $ 36.71万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8460926
• 关键词: Address; Amino Acids; Aminolevulinic Acid; Anabolism; Anemia; Binding; Biological Assay; Bone Marrow; Candidate Disease Gene; Carrier Proteins; Cell Line; Cells; Chromosome Mapping; Clinical; Clinical Research; Collaborations; Complement; Copy Number Polymorphism; Coupling; Cytochromes; DNA; Data; Databases; Defect; Dietary Supplementation; Disease; Dysmyelopoietic Syndromes; Enzymes; Erythrocytes; Erythroid; Event; Family; Gene Expression Profile; Genes; Genetic; Genome; Genotype; Glycine; Grant; Heme; Heme Iron; Hemoglobin; Human; Inborn Genetic Diseases; Inherited; Inner mitochondrial membrane; Iron; Iron Metabolism Disorders; Iron Overload; Knowledge; Laboratories; Learning; Link; Liposomes; Mammalian Cell; Mammals; Maps; Metabolism; Mitochondria; Modeling; Molecular; Molecular Genetics; Mus; Mutate; Mutation; Orthologous Gene; Oxygen; Pathogenesis; Pathologic; Pathway interactions; Patients; Phase; Phenotype; Physiological; Play; Production; Protein Family; Proteins; Reaction; Recruitment Activity; Refractory Anemia with Ringed Sideroblasts; Resources; Role; Sampling; Sideroblastic Anemia; Single Nucleotide Polymorphism; Site; Somatic Mutation; Stem cells; Sulfur; Techniques; Testing; Tissues; Yeasts; cofactor; cohort; dietary supplements; exome; genome sequencing; genome wide association study; genome-wide; heme biosynthesis; insight; iron deficiency; iron metabolism; member; neoplastic; novel; overexpression; patient registry; positional cloning; public health relevance; reconstitution; solute

DESCRIPTION (provided by applicant): The major site of iron utilization in mammalian cells is the mitochondrion. Mitochondria are instrumental in the biosynthesis of heme and iron sulfur clusters, which contain iron, and are employed as cofactors in numerous proteins, including hemoglobin, the cytochromes, and many enzymes that play roles in key metabolic processes. The vast majority of iron in mammals is present as heme, primarily in hemoglobin in erythrocytes, underscoring the importance of understanding mitochondrial iron utilization to describing the normal pathways of iron metabolism. Disorders of iron and heme metabolism are prevalent in humans, and are most commonly the consequence of systemic iron deficiency or iron overload. The sideroblastic anemias (SAs) are an uncommon, but informative, group of diseases associated with ineffective mitochondrial iron utilization and pathologic mitochondrial iron accumulation. In collaboration, we have identified mutations in the mitochondrial solute carrier protein family 25, member A38 (SLC25A38) as an autosomal recessive cause of inherited congenital sideroblastic anemia (CSA) that is clinically very similar to X-linked sideroblastic anemia due to mutations in the heme synthesis enzyme 5- aminolevulinic acid (ALA) synthase. We have developed preliminary data indicating that, like ALAS2, SLC25A38 is likely involved in mitochondrial heme biosynthesis. Specifically, evidence would suggest that SLC25A38 transports glycine, one of the substrates of the reaction catalyzed by ALAS2, into the erythroid mitochondrion to support very high-level heme synthesis. Furthermore, SLC25A28 may act by exchanging glycine for ALA across the mitochondrial inner membrane, coupling substrate import to product export, thereby streamlining the initial mitochondrial phase of heme biosynthesis. This grant endeavors to directly test these hypotheses. Furthermore, because the genetic cause of nearly half of cases of CSA go undiscovered, we propose developing a patient registry to complement our already large clinical research database of CSA patients and use these samples to go on to discover novel CSA loci using genome-wide screens. Acquired idiopathic (neoplastic) sideroblastic anemia, also called refractory anemia with ringed sideroblasts (RARS) is a myelodysplastic syndrome that is relatively more common (~7.5 new cases/yr/106 people) than CSA. As perplexing as CSA is, RARS is more so, as we know very little about its pathogenesis, and much less about the somatic molecular genetic events that underlie this phenotype. Here, we will attempt to leverage our knowledge of the CSAs to gain insight into the pathogenesis of RARS. Furthermore, we will independently address the dearth of information regarding the molecular underpinnings of RARS by sequencing entire genomes. In both cases, we expect to learn more about mitochondrial iron metabolism, the SAs and approaches to therapy.

描述（由申请人提供）：哺乳动物细胞中铁利用的主要部位是线粒体。线粒体在血红素和铁硫簇（含有铁）的生物合成中发挥着重要作用，并被用作多种蛋白质的辅助因子，包括血红蛋白、细胞色素和许多在关键代谢过程中发挥作用的酶。哺乳动物中的绝大多数铁以血红素的形式存在，主要存在于红细胞的血红蛋白中，这强调了了解线粒体铁利用对于描述铁代谢正常途径的重要性。铁和血红素代谢紊乱在人类中普遍存在，最常见的是全身性缺铁或铁过载的结果。铁粒幼细胞贫血 (SA) 是一组罕见但信息丰富的疾病，与无效的线粒体铁利用和病理性线粒体铁积累相关。通过合作，我们发现线粒体溶质载体蛋白家族 25 成员 A38 (SLC25A38) 中的突变是遗传性先天性铁粒幼细胞贫血 (CSA) 的常染色体隐性病因，该贫血在临床上与由于血红素合成酶 5-氨基乙酰丙酸 (ALA) 突变导致的 X 连锁铁粒幼细胞贫血非常相似 合酶。我们已经开发出初步数据，表明与 ALAS2 一样，SLC25A38 可能参与线粒体血红素生物合成。具体来说，有证据表明，SLC25A38 将甘氨酸（ALAS2 催化反应的底物之一）转运到红细胞线粒体中，以支持非常高水平的血红素合成。此外，SLC25A28 可能通过跨线粒体内膜将甘氨酸交换为 ALA 来发挥作用，将底物输入与产物输出耦合，从而简化血红素生物合成的初始线粒体阶段。这笔赠款致力于直接检验这些假设。此外，由于近一半 CSA 病例的遗传原因未被发现，我们建议开发一个患者注册表，以补充我们已经庞大的 CSA 患者临床研究数据库，并使用这些样本继续通过全基因组筛选发现新的 CSA 位点。获得性特发性（肿瘤性）铁粒幼细胞贫血，也称为环状铁粒幼细胞难治性贫血 (RARS) 是一种骨髓增生异常综合征，比 CSA 相对更常见（约 7.5 个新病例/年/106 人）。与 CSA 一样令人困惑的是，RARS 更令人困惑，因为我们对其发病机制知之甚少，对这种表型背后的体细胞分子遗传事件知之甚少。在这里，我们将尝试利用我们对 CSA 的了解来深入了解 RARS 的发病机制。此外，我们将通过对整个基因组进行测序来独立解决有关 RARS 分子基础信息缺乏的问题。在这两种情况下，我们希望了解更多有关线粒体铁代谢、SA 和治疗方法的信息。