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Letters to the Editor
S1D). Nonetheless, the absence of oxidative phosphoryla- tion or mitochondrial protein synthesis defect observed in the context of SARS2 inactivation is in accordance with the lack of clear biochemical phenotypes previously reported in skin fibroblasts and myoblasts from most of mutant mt- aaRS patients.6
Despite their common biochemical role in mitochondrial protein synthesis, mutations of the mt-aaRS family have been correlated to a wide range of clinical manifestations. To date, three mt-aaRS defects affecting the tyrosyl-tRNA synthetase 2 (YARS2),11 the leucyl-tRNA synthetase 2 (LARS2)12 and the isoleucyl-tRNA synthetase 2 (IARS2)3 genes have been associated with erythroid disorders corre- sponding to CSA.
It is now well established that mitochondria are involved in erythroid cells homeostasis through multiple ways, such as heme synthesis, apoptosis, and cell differentiation fol- lowing transient caspase activation. Alteration of these mitochondrial functions can therefore lead to a variety of erythroid disorders.13 For instance, it has been reported that alteration of physiological pathways involving caspases and mitochondria in myelodysplastic syndromes leads to abnormal activation of a mitochondria-mediated apoptotic pathway in erythroid cells and therefore to an ineffective erythropoiesis.14 Accordingly, our results suggest that the non-regenerative anemia observed in the SARS2-mutated patients may be related to an exacerbation of the mito- chondria-mediated apoptotic pathway. However, the rea- son why only few defects in mt-aaRS including SARS2 result in perturbed erythropoiesis remains to be elucidated. With regard to tissue specificity of the different mt-aaRS mutations, one can hypothesize that non-translational functions only crucial in some tissues or cells are specific to each mt-aaRS. It is also possible that the remaining residual activity of some mt-aaRS is sufficient to maintain mito- chondrial function in most cell types but not in specific tis- sues.
In summary, our results strongly suggest that SARS2 is a new gene involved in CSA, although concomitant heredi- tary spherocytosis, through chronic stress erythropoiesis, has potentially exacerbated the hematological phenotype in the present case. We therefore consider that SARS2 should be added to the list of genes which have to be explored in patients presenting with sideroblastic anemia in early childhood. Our study also emphasizes the rele- vance of performing next generation sequencing in patients presenting with severe undiagnosed anemia associated with extra hematological signs to identify new key actors of physiological erythropoiesis.
Elia Colin,1 Geneviève Courtois,1 Chantal Brouzes,2
Juliette Pulman,3 Marion Rabant,4 Agnès Rötig,3 Hélène Taffin,5 Mathilde Lion-Lambert,5 Sylvie Fabrega,6 Lydie Da Costa,7 Mariane De Montalembert,8 Rémi Salomon,5 Olivier Hermine9
10 and Lucile Couronné
1Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications, INSERM U1163, Imagine Institute, University of Paris, Laboratory of Excellence GR-Ex; 2Hematology Laboratory, Hôpital Necker-Enfants Malades, Assistance publique-Hôpitaux de Paris (AP-HP); 3Laboratory for Genetics of Mitochondrial Disorders, INSERM U1163, Imagine Institute, University of Paris; 4Department of Pathology, Hôpital Necker - Enfants Malades, Assistance Publique-Hôpitaux de Paris, University of Paris; 5Department of Pediatric Nephrology, MARHEA, Hôpital Necker - Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP); 6VVTG platform, SFR Necker; 7Hematology Laboratory, Robert Debré Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), University of Paris, Laboratory of Excellence GR-Ex;
8Department of General Pediatrics and Pediatric Infectious Diseases, Reference Center for Sickle Cell Disease, Hôpital Necker - Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Université de Paris; 9Hematology Department, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris (APHP), Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM U1163, Imagine Institute, University of Paris, Laboratory of Excellence GR-Ex and 10Laboratory of Onco-Hematology, Hôpital Necker - Enfants Malades, Assistance Publique - Hôpitaux de Paris (APHP), Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutical Implications, INSERM U1163, Imagine Institute, University of Paris, Laboratory of Excellence GR-Ex, Paris, France
Correspondence:
ELIA COLIN - elia.colin@hotmail.fr doi:10.3324/haematol.2021.279138 Received: May 11, 2021.
Accepted: July 26, 2021.
Pre-published: August 19, 2021. Disclosures: no conflicts of interest to disclose.
Contributions: EC, OH and LC designed the study; HT, ML-L, MdM, LDC and RS were responsible for patient management and collection of clinical and laboratory data; MR conducted histopathologi- cal analyses; EC, GC and JP designed experiments; EC performed experiments; EC and LC analyzed data and co-wrote the manuscript. All the authors reviewed the manuscript and approved the final version.
Funding: this study was supported by grants from Laboratory of Excellence GR-Ex, reference ANR-11-LABX-0051. The labex GR- Ex is funded by the IdEx program “Investissements d’avenir” of the French National Research Agency, reference ANR-18-IDEX-0001.
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