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

Abstract

SummaryGermline 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 (<1%) in IVS4 (c.587+21A>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.

Challenges in Diagnosing Myelodysplastic Syndromes in the Era of Genetic Testing: Proceedings of the 13th Workshop of the European Bone Marrow Working Group

“…The derived USB1 protein has a role in RNA processing. Acquired mutations in USB1 have been observed in a small subset (2/140 tested cases) of haematopoietic malignancies, supporting the role of the USB1 gene in the development of myeloid neoplasms [40].…”

The Role of Genetic Testing in Hereditary Poikiloderma: A Case Report

“…10 In cases where hematopoietic stem cell transplantation may be required, molecular genetic studies can aid in the selection of healthy sibling donors, highlighting the value of these studies in planning management.…”

“…Little is known about USB1 mutations in acquired myelodysplastic syndrome, although mutations in the splicesome machinery are recognized in leukemogenesis. 10 The defective USB1 gene affects myeloid hemostasis and…”

“…neutrophil maturation and reports of myelodysplastic syndrome and acute myeloid leukemia support the classification of PN as a bone marrow failure syndrome with a predisposition to malignancies. 10 In cases where hematopoietic stem cell transplantation may be required, molecular genetic studies can aid in the selection of healthy sibling donors, highlighting the value of these studies in planning management.…”

Variant snRNPs: New players within the spliceosome system

“… 45 Myeloid cells are particularly sensitive and defects impact on skin and bone tissues especially. 46 , 47 While disruption of U6 3' end processing is evident in PN patients and USB1-deficient cells, deep RNA sequencing (RNA-seq) analysis of PN lymphoblastoid cells revealed no significant changes in U6 steady state levels and no obvious defects in splicing. 43 , 44 In contrast, morpholino inactivation of MPN1 in yeast resulted in global defects in pre-mRNA splicing, which could be reversed upon overexpression of U6.…”