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ZRSR2, an X-linked component of the minor spliceosome, is recurrently mutated in myelodysplastic syndrome (MDS), a clonal hematopoietic disorder characterized by ineffective hematopoiesis and peripheral cytopenias. Somatic loss-of-function and splice-site mutations in ZRSR2 have been reported in independent MDS cohorts, underscoring its role as a founder lesion in a subset of patients. Functional assays demonstrate that ZRSR2 deficiency selectively impairs U12-type intron removal, causing intron retention in key transcripts and altering differentiation of myeloid and erythroid progenitors. Clinically, isolated ZRSR2 mutations present with transfusion-dependent macrocytic anemia in the absence of additional high-risk cytogenetic or molecular features, whereas co-occurring spliceosome or epigenetic gene mutations modulate prognosis and transformation risk.
In a cohort of 193 MDS patients, ZRSR2 mutations were identified in 6 individuals (3.1%) (PMID:22389253), while analysis of 221 patients revealed splice gene mutations in 95 cases, with ZRSR2 contributing to the intermediate-risk MDS subgroup (PMID:22343920). A series of five patients with isolated ZRSR2 loss-of-function mutations exhibited persistent, transfusion-dependent macrocytic anemia without leukopenia or thrombocytopenia, and a low risk of progression to acute leukemia (PMID:28942350). These data establish ZRSR2 as a recurrent somatic target in MDS and define a distinct genotype–phenotype correlation.
The spectrum of ZRSR2 variants includes point mutations disrupting splice-site recognition and frameshift indels. A representative frameshift allele, c.1211_1212del (p.Gly404GlufsTer23), abrogates minor spliceosome assembly and exemplifies the loss-of-function mechanism common to X-linked splice factor mutations. ZRSR2 mutations co-occur with TET2, ASXL1, and other epigenetic regulators, suggesting cooperative clonal evolution, yet may act as founding events in disease initiation.
Mechanistic studies using shRNA knockdown show that ZRSR2 depletion leads to widespread retention of U12-type introns, while U2-dependent splicing remains largely intact (PMID:25586593). Murine Zrsr2 knockout models exhibit moderate U12 intron retention mitigated by compensation from the paralog Zrsr1, highlighting species-specific redundancy and confirming the essential role of ZRSR2 in minor splicing (PMID:33691379). These experiments link aberrant splicing to impaired myelopoiesis and support a haploinsufficient tumor suppressor model.
No conflicting evidence has been reported to dispute the role of ZRSR2 in MDS. Variants are consistently absent in germline controls, and functional rescue of splicing defects reverses differentiation abnormalities, reinforcing causality. Although additional spliceosome components (SF3B1, SRSF2, U2AF1) contribute to MDS heterogeneity, ZRSR2 mutations define a unique subset with potential prognostic and therapeutic implications.
Integration of genetic and functional data confirms a Strong gene–disease association: ZRSR2 mutations are recurrent in unrelated MDS patients, induce consistent molecular defects in minor intron splicing, and produce a characteristic macrocytic anemia phenotype. Clinically, screening for ZRSR2 facilitates risk stratification, informs surveillance for transformation, and identifies candidates for spliceosome-targeted therapies. Key Take-home: ZRSR2 mutation testing refines diagnosis of MDS subtypes and guides personalized management strategies.
Gene–Disease AssociationStrongRecurrent ZRSR2 mutations identified in 6/193 MDS patients and in splice gene panels of 221 patients, with consistent absence in germline cohorts Genetic EvidenceModerateSomatic ZRSR2 mutations in independent MDS cohorts (6 probands; 95 splice gene–mutant cases) and 5 isolated LoF cases with macrocytic anemia Functional EvidenceModerateshRNA and knockout models demonstrate U12-type intron retention and hematopoietic differentiation defects |