Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Impaired Mitochondrial Function and Marrow Failure in Patients Carrying a Variant on SRSF4 Gene

Maurizio Miano
ORCID logo ,
Nadia Bertola
ORCID logo ,
Alice Grossi
,
Gianluca Dell'Orso
,
Stefano Regis
ORCID logo ,
Marta Rusmini
ORCID logo ,
Paolo Uva
ORCID logo ,
Diego Vozzi
,
Francesca Fioredda
,
Elena Palmisani
,
Michela Lupia
ORCID logo ,
Marina Lanciotti
,
Federica Grilli
,
Fabio Corsolini
,
Luca Arcuri
,
Maria Carla Giarratana
,
Isabella Ceccherini
,
Carlo Dufour
,
Enrico Cappelli
* ,
Silvia Ravera
ORCID logo
Version 1 : Received: 13 December 2023 / Approved: 13 December 2023 / Online: 14 December 2023 (08:07:53 CET)

A peer-reviewed article of this Preprint also exists.

Miano, M.; Bertola, N.; Grossi, A.; Dell’Orso, G.; Regis, S.; Rusmini, M.; Uva, P.; Vozzi, D.; Fioredda, F.; Palmisani, E.; Lupia, M.; Lanciotti, M.; Grilli, F.; Corsolini, F.; Arcuri, L.; Giarratana, M.C.; Ceccherini, I.; Dufour, C.; Cappelli, E.; Ravera, S. Impaired Mitochondrial Function and Marrow Failure in Patients Carrying a Variant of the SRSF4 Gene. Int. J. Mol. Sci. 2024, 25, 2083. Miano, M.; Bertola, N.; Grossi, A.; Dell’Orso, G.; Regis, S.; Rusmini, M.; Uva, P.; Vozzi, D.; Fioredda, F.; Palmisani, E.; Lupia, M.; Lanciotti, M.; Grilli, F.; Corsolini, F.; Arcuri, L.; Giarratana, M.C.; Ceccherini, I.; Dufour, C.; Cappelli, E.; Ravera, S. Impaired Mitochondrial Function and Marrow Failure in Patients Carrying a Variant of the SRSF4 Gene. Int. J. Mol. Sci. 2024, 25, 2083.

Abstract

Serine/arginine-rich splicing factors (SRSF) are a family of proteins involved in RNA metabolism, including pre-mRNA constitutive and alternative splicing. The role of SRSF proteins on mitochondria activity has already been shown for SRSF6 but SRSF4 altered expression has never been reported as disease causing. An 8-year-old patient admitted to the Hematology Unit because of leukopenia, lymphopenia, and neutropenia showed a missense variant of unknown significance on the SRSF4 gene (p.R235W) found by Whole Genome Sequencing analysis and inherited by the mother who suffered from mild leuko-neutropenia. Both patients showed lower SRSF4 protein expression compared to HD and altered mitochondrial function and energetic metabolism, which appeared associated with low mTOR phosphorylation and an imbalance in proteins regulating biogenesis (i.e., CLUH) and mitochondrial dynamics (i.e., DRP1, OPA1). Transfection with the wt-SRSF4 gene restored the mitochondrial function. In conclusion, this study shows that the de-scribed variant of the SRSF4 gene is pathogenetic and causes reduced SRSF4 protein expression, which leads to cells’ mitochondrial function impairment. Since mitochondrial function is crucial for hematopoietic stem cells maintenance and some genetic bone marrow failure syndromes display mitochondrial defects, SRSF4 mutation could have substantially contribute to the clinical phenotype of our patient.

Keywords

Marrow failure; mitochondria; SRSF4; mTOR; CLUH; DRP1; OPA1

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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