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。线粒体在血红素和含铁硫簇的生物合成中起作用，并在许多蛋白质中用作辅因子，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。哺乳动物中绝大多数铁以血红素形式存在，主要存在于红细胞中的血红蛋白中，这强调了理解线粒体铁利用率以描述铁代谢的正常途径的重要性。铁和血红素代谢紊乱在人类中普遍存在，并且最常见的是系统性铁缺乏或铁过载的结果。铁粒幼细胞性贫血（SA）是一种罕见的，但信息，一组疾病与无效的线粒体铁利用和病理性线粒体铁积累。在合作中，我们已经确定了突变的线粒体溶质载体蛋白家族25，成员A38（SLC25A38）作为遗传性先天性铁粒幼细胞性贫血（CSA）的常染色体隐性病因，临床上非常相似的X-连锁铁粒幼细胞性贫血由于血红素合成酶5-氨基乙酰丙酸（ALA）合酶的突变。我们已经开发了初步的数据表明，像ALAS2，SLC25A38可能参与线粒体血红素的生物合成。具体而言，有证据表明，SLC25A38转运甘氨酸（ALAS2催化的反应底物之一）进入红系红细胞，以支持非常高水平的血红素合成。此外，SLC25A28可以通过跨线粒体内膜将甘氨酸交换为ALA，将底物输入耦合到产物输出，从而简化血红素生物合成的初始线粒体阶段。本研究旨在直接验证这些假设。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登记处，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使用全基因组筛选发现新的CSA基因座。获得性特发性（肿瘤性）铁粒幼细胞性贫血，也称为难治性贫血伴环状铁粒幼细胞（RARS），是一种骨髓增生异常综合征，比CSA相对更常见（约7.5例新发病例/年/106人）。尽管CSA令人困惑，但RARS更是如此，因为我们对其发病机制知之甚少，更不了解这种表型背后的体细胞分子遗传事件。在这里，我们将试图利用我们的知识的CSA，以深入了解RARS的发病机制。此外，我们将通过对整个基因组进行测序，独立解决有关RARS分子基础的信息缺乏的问题。在这两种情况下，我们希望了解更多关于线粒体铁代谢，SA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.