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Kermasson L, Churikov D, Awad A, et al. Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects. Blood. 2022;doi: 10.1182/blood.2021010791.
Kermasson, L., Churikov, D., Awad, A., Smoom, R., Lainey, E., Touzot, F., Audebert-Bellanger, S., Haro, S., Roger, L., Costa, E., Mouf, M., Bottero, A. J., Oleastro, M., Abdo, C., de Villartay, J. P., Géli, V., Tzfati, Y., Callebaut, I., Danielian, S., Soares, G., Kannengiesser, C., & Revy, P. (2022). Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects. Blood, . https://doi.org/10.1182/blood.2021010791
Kermasson, Laëtitia, et al. "Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects." Blood vol. (2022). doi: https://doi.org/10.1182/blood.2021010791
Kermasson L, Churikov D, Awad A, Smoom R, Lainey E, Touzot F, Audebert-Bellanger S, Haro S, Roger L, Costa E, Mouf M, Bottero AJ, Oleastro M, Abdo C, de Villartay JP, Géli V, Tzfati Y, Callebaut I, Danielian S, Soares G, Kannengiesser C, Revy P. Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects. Blood. 2022 Jan 10; doi: 10.1182/blood.2021010791. Epub 2022 Jan 10. PMID: 35007328.
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Blood. 2022 Jan 10; doi: 10.1182/blood.2021010791. Epub 2022 Jan 10.

Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects.

Blood

Laëtitia Kermasson, Dmitri Churikov, Aya Awad, Riham Smoom, Elodie Lainey, Fabien Touzot, Séverine Audebert-Bellanger, Sophie Haro, Laureline Roger, Emilia Costa, Maload Mouf, Adriana Jorgelina Bottero, Matias Oleastro, Chrystelle Abdo, Jean-Pierre de Villartay, Vincent Géli, Yehuda Tzfati, Isabelle Callebaut, Silvia Danielian, Gabriela Soares, Caroline Kannengiesser, Patrick Revy

Affiliations

  1. Institut IMAGINE UMR1163, Paris, France.
  2. Marseille Cancer Research Center, Marseille, France.
  3. The Silberman Institute of Life Science, Jerusalem, Israel.
  4. AP-HP - Hopital Robert Debré, Paris, France.
  5. CHU Sainte-Justine, Montréal, Canada.
  6. Department of medical genetics,, Brest, France.
  7. Department of paediatrics, Brest, France.
  8. Muséum National d'Histoire Naturelle, Paris, France.
  9. Centro Hospitalar e Universitário do Porto, Porto, Portugal.
  10. Zenon Skelter Institute, Eggum, Norway.
  11. Servicio de Gastroenterología. Hospital de Pediatría, buenos aires, Argentina.
  12. Garrahan Hospital, Buenos Aires, Argentina.
  13. Hopital Necker, Université de Paris, Paris, France.
  14. INSERM UMR1163, Paris, France.
  15. U1068 Inserm, UMR7258 CNRS, Aix-Marseille University, Institut Paoli-Calmettes, Marseille, France.
  16. The Hebrew University of Jerusalem, Jerusalem, Israel.
  17. Sorbonne University, CNRS UMR7590, Museum National d'Histoire Naturelle, Paris, France.
  18. "Juan Pedro Garrahan" National Hospital of Pediatrics, Buenos Aires, Argentina.
  19. Centro de Genética Médica Jacinto de Magalhães, Porto, Portugal.
  20. APHP, Hopital Xavier Bichat, Service de Génétique, paris, France.
  21. Imagine Institute for Genetic Diseases, Paris, France.

PMID: 35007328 DOI: 10.1182/blood.2021010791

Abstract

Inherited bone marrow failure syndromes (IBMFS) represent a group of disorders typified by impaired production of one or several blood cell types. The telomere biology disorders dyskeratosis congenita (DC) and its severe variant Høyeraal-Hreidarsson (HH) syndrome are rare IBMFS characterized by bone marrow failure, developmental defects, and various premature aging complications associated with critically short telomeres. Here we identified biallelic variants in the gene encoding the 5'-to-3' DNA exonuclease Apollo/SNM1B in three unrelated patients presenting with a DC/HH phenotype consisting of early onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly and/or intrauterine growth retardation. All three patients carry a homozygous or compound heterozygous (in combination with a null-allele) missense variant affecting the same residue L142 (L142F or L142S) located in the catalytic domain of Apollo. Apollo-deficient cells from patients exhibited spontaneous chromosome instability and impaired DNA repair that was complemented by CRISPR/Cas9-mediated gene correction. Furthermore, patients' cells showed signs of telomere fragility that were however not associated with global reduction of telomere length. Unlike patients' cells, human Apollo KO HT1080-cell lines showed strong telomere dysfunction accompanied by excessive telomere shortening, suggesting that the L142S and L142F Apollo variants are hypomorphic. Collectively, these findings define human Apollo as a genome caretaker and identify biallelic Apollo variants as a genetic cause of a hitherto unrecognized severe IBMFS combining clinical hallmarks of DC/HH with normal telomere length.

Copyright © 2022 American Society of Hematology.

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