# Impaired Mitochondrial Function and Marrow Failure in Patients Carrying a Variant of the SRSF4 Gene

## TL;DR

A genetic variant in the SRSF4 gene causes mitochondrial dysfunction and bone marrow failure in a patient and their mother.

## Contribution

This is the first report linking SRSF4 gene variants to mitochondrial dysfunction and marrow failure.

## Key findings

- The SRSF4 p.R235W variant reduces SRSF4 protein expression and impairs mitochondrial function.
- Restoring SRSF4 expression with the wild-type gene reversed mitochondrial dysfunction.
- Mitochondrial defects in SRSF4 carriers are linked to mTOR signaling and biogenesis/dynamics imbalances.

## Abstract

Serine/arginine-rich splicing factors (SRSFs) are a family of proteins involved in RNA metabolism, including pre-mRNA constitutive and alternative splicing. The role of SRSF proteins in regulating mitochondrial activity has already been shown for SRSF6, but SRSF4 altered expression has never been reported as a cause of bone marrow failure. An 8-year-old patient admitted to the hematology unit because of leukopenia, lymphopenia, and neutropenia showed a missense variant of unknown significance of the SRSF4 gene (p.R235W) found via whole genome sequencing analysis and inherited from the mother who suffered from mild leuko-neutropenia. Both patients showed lower SRSF4 protein expression and altered mitochondrial function and energetic metabolism in primary lymphocytes and Epstein–Barr-virus (EBV)-immortalized lymphoblasts compared to healthy donor (HD) cells, which appeared associated with low mTOR phosphorylation and an imbalance in the proteins regulating mitochondrial biogenesis (i.e., CLUH) and dynamics (i.e., DRP1 and OPA1). Transfection with the wtSRSF4 gene restored mitochondrial function. In conclusion, this study shows that the described variant of the SRSF4 gene is pathogenetic and causes reduced SRSF4 protein expression, which leads to mitochondrial dysfunction. Since mitochondrial function is crucial for hematopoietic stem cell maintenance and some genetic bone marrow failure syndromes display mitochondrial defects, the SRSF4 mutation could have substantially contributed to the clinical phenotype of our patient.