Clinical Research Directory

Genomic of CONgenital Sideroblastic Anemias

Congenital sideroblastic anemias (CSA) are a group of rare disorders characterized by abnormal iron utilization during erythropoiesis, leading to mitochondrial iron overload, the formation of ring sideroblasts, and ineffective erythropoiesis resulting in anemia. Ring sideroblasts are erythroid precursors that contain non-heme iron deposits in their mitochondria, forming a distinctive ring-like pattern around the nucleus. Mitochondria are double membrane organelle provide a large amount of energy for cellular activities, by the process of oxidative phosphorylation (OXPHOS). The role of mitochondria has been well described in erythropoiesis. CSA exhibits clinical heterogeneity, affecting only the erythroid system in some cases, while in others presenting as part of broader syndromic conditions. Their molecular basis remains imperfectly known, although the development of next- generation sequencing technology brought tremendous advances in the understanding of their genetic features. More than 20 genes have been identified as causative of CSA, with all modes of inheritance observed: X-linked recessive, autosomal dominant, autosomal recessive, pseudo- dominant, and mitochondrial. These genes are typically involved in one of four key mitochondrial pathways: i) Heme biosynthesis (e.g., ALAS2, SLC25A38); ii) Iron-sulfur cluster biosynthesis and transport (e.g., GLRX5, HSPA9, HSCB); iii) tRNA synthesis and maturation (e.g., PUS1, YARS2, LARS2, IARS2, SARS2, MARS1, TRNT1); iv) Mitochondrial respiratory chain synthesis (e.g., NDUFB11). However, in nearly 30% of cases within the French CSA cohort, the underlying genetic cause remains unknown. In these patients with molecularly unexplained whole genome or exome sequencing approaches focusing on genes involved in mitochondrial function and iron metabolism identified several possibly pathogenic variants in CSA patients. These genes were not clearly described as playing a role in erythropoiesis or heme or iron metabolism. We hope to confirm their role in CSA. However, in nearly 30% of cases within the French CSA cohort , the underlying genetic cause remains unknown. The investigators hope to confirm the role in CSA of gene identified with exome sequencing approaches.

POlycythemia, Proteins and ErYthropoiesis

Erythropoiesis encompasses all the stages and mechanisms involved in the production of red blood cells, or erythrocytes, under the control of a large number of regulatory agents, most often proteins. Among these proteins, erythropoietin and interleukin-3 play a major role. Similarly, proteins involved in iron metabolism (erythroferrone, hepcidin, ferroportin, transferrin, ferritin) influence erythrocyte production more or less directly. The regulation of erythropoiesis is a fine, complex mechanism involving a large number of players, not only through the stimulation of hypoxia pathways to control erythropoietin synthesis, but also through the availability of iron, an essential element for erythropoiesis. Excessive erythrocyte production can lead to polycythemia, the causes of which are varied, primary or secondary, acquired or constitutional. The aim of this work is the descriptive study (quantitative and/or qualitative) of the various proteins involved in the regulation of erythropoiesis in patients with polycythemia. These proteins will be measured in the plasma of patients obtained after blood sampling or bloodletting (bloodletting being the most common treatment for polyglobulic patients) and will be compared with the proteins of patients without polycythemia.