Molecular Genetics of Sideroblastic Anemia

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。线粒体在含铁的血红素和铁硫簇的生物合成中起着重要作用，并且是许多蛋白质的辅助因子，包括血红蛋白、细胞色素和许多在关键代谢过程中起作用的酶。哺乳动物体内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很普遍，最常见的是全身铁缺乏或铁超载的结果。铁母细胞贫血（SAs）是一种罕见的，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有关。在合作中，我们发现线粒体溶质载体蛋白家族25成员A38 （SLC25A38）的突变是遗传性先天性铁母细胞性贫血（CSA）的常染色体隐性原因，由于血红素合成酶5-氨基乙酰丙酸（ALA）合成酶的突变，临床上与x连锁铁母细胞性贫血非常相似。我们已经开发的初步数据表明，SLC25A38可能与ALAS2一样参与线粒体血红素的生物合成。具体来说，有证据表明SLC25A38将甘氨酸（ALAS2催化反应的底物之一）转运到红系线粒体，以支持非常高水平的血红素合成。此外，SLC25A28可能通过线粒体内膜将甘氨酸交换为ALA，偶联底物进口和产品出口，从而简化血红素生物合成的线粒体初始阶段。这项拨款旨在直接检验这些假设。此外，由于近一半CSA病例的遗传原因未被发现，我们建议建立一个患者登记处，以补充我们已经庞大的CSA患者临床研究数据库，并利用这些样本继续使用全基因组筛选发现新的CSA位点。获得性特发性（肿瘤性）铁母细胞贫血，也称为难治性贫血伴环状铁母细胞（RARS），是一种比CSA更常见的骨髓增生异常综合征（约7.5例/年/106人）。与CSA一样令人费解的是，RARS更是如此，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，我们将通过全基因组测序来独立解决关于RARS分子基础的信息缺乏问题。在这两种情况下，我们希望更多地了解线粒体铁代谢，SAs和治疗方法。

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.