MMS22L is a novel key actor of normal and pathological erythropoiesis
The emergence of next-generation sequencing techniques has led to the genetic characterization of numerous congenital erythroid disorders, emphasizing crucial pathways in both normal and pathological erythropoiesis. In this study, whole exome sequencing of a single patient with atypical congenital pure red cell aplasia revealed a mutation in the <i>CDAN1</i> gene, typically associated with congenital dyserythropoietic anemia type 1 (CDAI), together with a previously unreported mutation in the <i>MMS22L</i> gene. Combined <i>mms22l</i> and <i>cdan1</i> haploinsufficiency results in severe anemia in a zebrafish model. In human erythroid progenitors, loss of <i>MMS22L</i> leads to proliferation and differentiation arrest associated with activation of the p53 pathway and global epigenetic alterations, showing that MMS22L plays an indispensable role in erythropoiesis. Furthermore, MMS22L and CDAN1 are involved in the same protein complex whose nuclear import is mediated by the importin 4 (IPO4) protein, and MMS22L nuclear import is impaired in CDAI patients due to a defective interaction between CDAN1 and IPO4. Overall, through the genetic description of a single case characterized by digenic inheritance, we identified MMS22L as a novel key factor in erythropoiesis and brought new insights into normal erythropoiesis regulation and CDAI pathophysiology.
Authors
- W Vainchenker
- Dror Bar (ORCID: https://orcid.org/0000-0003-3276-9941)
- Jan Frayne
- Elia Colin
- Chantal Brouzes (ORCID: https://orcid.org/0000-0001-7550-1270)
- A. Miccio
- Mohammed Zarhrate (ORCID: https://orcid.org/0000-0001-5821-2629)
- M Colard (ORCID: https://orcid.org/0000-0001-8247-0505)
- Elisa Bayard
- G. Courtois (ORCID: https://orcid.org/0000-0001-6370-5575)
- Sandra Manceau (ORCID: https://orcid.org/0000-0003-1836-2002)
- Thiago Maciel Trovati
- Sophie Park (ORCID: https://orcid.org/0000-0002-1521-2052)
- Lucile Couronné (ORCID: https://orcid.org/0000-0002-1357-5482)
- Jean Soulier (ORCID: https://orcid.org/0000-0002-8734-5356)
- Olivier Hermine (ORCID: https://orcid.org/0000-0003-2574-3874)
- Mohammad Salma (ORCID: https://orcid.org/0000-0002-3648-1809)
- Éric Soler (ORCID: https://orcid.org/0000-0003-0521-7463)
- Michaël Dussiot (ORCID: https://orcid.org/0000-0002-6804-1621)
- Carine Lefèvre (ORCID: https://orcid.org/0000-0003-3590-2445)
- Charlotte Andrieu‐Soler (ORCID: https://orcid.org/0000-0002-3287-6117)
- Liran Shlush
- Patrick Mayeux
- L Da Costa
- Benjamin Carpentier
- Emilie‐Fleur Gautier
- Ivan Ferrer‐Vicens
- Slim Azouzi
- Anne Lambilliotte
- Romain Duval
- Alicia Fernandes
Institutions
- Délégation Paris 5 (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Catholique de Lille (FR)
- Université de Montpellier (FR)
- Université Paris Cité (FR)
- Centre Hospitalier Universitaire de Grenoble (FR)
- Institut Gustave Roussy (FR)
- Saint Louis University Hospital (US)
- University of Bristol (GB)
- Lille’s Cardiology Hospital (FR)
- Sorbonne Paris Cité (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Institut de Génétique Moléculaire de Montpellier (FR)
- Hôpital Robert-Debré (FR)
- Établissement Français du Sang (FR)
- Société Française de Rhumatologie (FR)
- Institut Cochin (FR)
- Hôpital Saint-Louis (FR)
- Biologie intégrée du globule rouge et de l'Erythropoïèse (FR)
- Institut des Maladies Génétiques Imagine (FR)
- Weizmann Institute of Science (IL)
- Université Grenoble Alpes (FR)
Publication Details
- Journal
- HemaSphere
- Published
- 2025-12-01
- DOI
- https://doi.org/10.1002/hem3.70264
- Primary Topic
- Erythrocyte Function and Pathophysiology
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Institut des maladies génétiques Imagine
- Agence Nationale de la Recherche
- Fondation pour la Recherche Médicale
- Medical Research Council