Genetic mutations are permanent alterations within an organism’s DNA sequence. This DNA contains instructions for building proteins, which perform most cellular functions. A change in the DNA sequence can alter a protein’s structure and function, affecting cellular processes. Mutations vary in size and can arise spontaneously during cell division or from external factors like chemicals or radiation.
Understanding SRSF2
The SRSF2 protein, also known as splicing factor SC-35, plays a role in RNA splicing within human cells. It belongs to the serine/arginine-rich (SR) family of proteins, which modify messenger RNA (mRNA) precursors. RNA splicing involves precisely removing non-coding segments, called introns, from pre-mRNA molecules to yield mature mRNA. This mature mRNA then serves as the template for synthesizing functional proteins.
SRSF2 contributes to both standard and alternative pre-mRNA splicing. Its structure includes an RNA recognition motif (RRM) for binding to RNA sequences and a serine/arginine-rich (RS) domain for interacting with other splicing factors. These interactions are necessary for assembling the spliceosome, a cellular machinery that catalyzes splicing. By regulating the inclusion or exclusion of specific gene segments called exons, SRSF2 helps generate various proteins from a single gene.
The Nature of the SRSF2 Mutation
An SRSF2 mutation is a change in the SRSF2 gene’s DNA sequence. The most common mutations affect the proline residue at position 95 (P95), often replacing it with histidine (P95H), leucine (P95L), or arginine (P95R). This P95 residue is in a linker region connecting the protein’s RNA recognition motif (RRM) and RS domain. Although not part of the core RNA-binding region, this proline residue still contributes to the protein’s ability to bind specific RNA sequences.
Such a mutation alters the SRSF2 protein’s RNA-binding affinities. This altered binding specificity leads to widespread mis-splicing of hundreds of other genes. For instance, mutant SRSF2 (P95H) can incorrectly regulate splicing events, increasing or decreasing exon inclusion in the final mRNA product. Specific RNA motifs, like UCCAG and UGGAG, show altered binding by the mutated protein, correlating with changes in exon inclusion or exclusion. This dysfunctional splicing produces abnormal proteins or alters the quantities of correctly formed proteins, disrupting normal cellular processes, particularly in blood cell formation.
Diseases Associated with SRSF2 Mutation
SRSF2 mutations are identified in myeloid neoplasms, cancers affecting blood-forming cells in the bone marrow. These mutations are common in Myelodysplastic Syndromes (MDS), conditions where the bone marrow produces abnormal or insufficient blood cells, affecting 20% to 30% of patients. SRSF2 mutations are also found in over 50% of Chronic Myelomonocytic Leukemia (CMML) cases, a myeloid neoplasm with features of both MDS and myeloproliferative neoplasms (MPN). In Acute Myeloid Leukemia (AML), a more aggressive blood cancer, SRSF2 mutations are present in up to 25% of individuals.
These mutations are linked to unfavorable clinical outcomes in patients with MDS and AML, often with reduced overall survival. The mis-splicing activity of mutant SRSF2 contributes to disease progression by disrupting gene expression that regulates blood cell development. For example, SRSF2 mutations can impair hematopoietic cell differentiation, leading to dysfunctional blood cells. SRSF2 mutations often occur alongside other genetic changes, such as those in TET2 and ASXL1 genes, which can further influence disease features and prognosis. Identifying an SRSF2 mutation can help classify specific myeloid neoplasm subtypes.
Detection and Clinical Significance
Detecting SRSF2 mutations in a clinical setting involves genetic testing, such as next-generation sequencing. These methods identify specific DNA changes in the SRSF2 gene from patient samples, often bone marrow biopsies. Identifying SRSF2 mutations is important for diagnosis, especially in Chronic Myelomonocytic Leukemia (CMML), where they are frequently observed and aid in confirming a diagnosis.
The presence of an SRSF2 mutation also provides significant prognostic information, indicating a less favorable outlook for patients with MDS and AML. For instance, the 2022 European LeukemiaNet (ELN) risk stratification guidelines for AML include SRSF2 mutations in the adverse risk category, assuming no other favorable genetic factors are present. While specific targeted therapies for SRSF2 mutations are not yet broadly available, ongoing research explores new treatment avenues. Studies have investigated approaches like Rho kinase inhibitors, which show potential in influencing the cell cycle and survival of SRSF2-mutated AML cells. This research suggests future personalized medicine strategies and interventions for individuals with this mutation.