Expanding the role of the splicing USB1 gene from Poikiloderma with Neutropenia to acquired myeloid neoplasms

Summary Germline mutations of the U6 biogenesis 1 (USB1) gene underlie Poikiloderma with Neutropenia (PN), a rare autosomal recessive genodermatosis conferring an increased risk of myelodysplasia. Recent evidence highlights a key role of USB1 protein in the splicing process, but nothing is known about USB1 alterations in acquired myelodysplastic syndromes, even though mutations in the spliceosome machinery represent an ubiquitous pathway in leukaemogenesis. By molecular cytogenetics and direct sequencing, we searched for USB1 deletions/duplications and point mutations in 141 bone marrow DNA samples from patients with myelodysplastic syndromes (n = 126), myelodysplastic/myeloproliferative neoplasms (n = 12) and acute myeloid leukaemia (n = 3). Three unreported variants, two in USB1 5'UTR (c.-83G>T and c.-66A>G), one in IVS3 (c.450-68dupT) and one ( G/rs200924980) were detected. The germline nature could be proved for the c.-66A>G, but remains undefined for c.-83G>T and c.450-68dupT. Matched controls analysis did not reveal either 5' UTR variants in 290 chromosomes and Real-time polymerase chain reaction showed a slight reduction in bone marrow RNA levels of the patient with c.-66A>G. No USB1 rearrangements were detected by interphase fluorescence in situ hybridization. This pilot investigation on USB1 expanded the variations repertoire of this gene, identifying three novel sequence variants, the role of which need further investigations in myeloid malignancies.