title: Expanding the role of the splicing USB1 gene from Poikiloderma with Neutropenia to acquired myeloid neoplasms.
abstract: 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 (<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.
authors: Medical Genetics, Department of Health Sciences, University of Milan, Milan, Italy.
authors: Gloria
authors: G
authors: Negri
authors: Haematology Unit, Polo Unico S.M. Misericordia, Perugia, Italy.
authors: Barbara
authors: B
authors: Crescenzi
authors: Medical Genetics, Department of Health Sciences, University of Milan, Milan, Italy.
authors: Elisa Adele
authors: EA
authors: Colombo
authors: Medical Genetics, Department of Health Sciences, University of Milan, Milan, Italy.
authors: Laura
authors: L
authors: Fontana
authors: Haematology Unit, Polo Unico S.M. Misericordia, Perugia, Italy.
authors: Gianluca
authors: G
authors: Barba
authors: Pediatric Oncology Haematology Unit, University of Perugia, Polo Unico S.M. Misericordia, Perugia, Italy.
authors: Francesco
authors: F
authors: Arcioni
authors: Medical Genetics, Department of Health Sciences, University of Milan, Milan, Italy.
authors: Cristina
authors: C
authors: Gervasini
authors: Haematology Unit, Polo Unico S.M. Misericordia, Perugia, Italy.
authors: Cristina
authors: C
authors: Mecucci
authors: Medical Cytogenetics and Molecular Genetics Laboratory, Centro di Ricerche e Tecnologie Biomediche IRCCS, Istituto Auxologico Italiano, Milan, Italy.
authors: Lidia
authors: L
authors: Larizza
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007438:Introns / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D054437:Myelodysplastic-Myeloproliferative Diseases / Q000235:genetics*; D009503:Neutropenia / Q000235:genetics*; D010727:Phosphoric Diester Hydrolases / Q000235:genetics* / Q000502:physiology; D010865:Pilot Projects; D017354:Point Mutation; D012326:RNA Splicing; D060888:Real-Time Polymerase Chain Reaction; D012868:Skin Abnormalities / Q000235:genetics*; D055815:Young Adult
chemical_list: D020121:5' Untranslated Regions; D010727:Phosphoric Diester Hydrolases; C576020:USB1 protein, human
keywords: USB1 point mutations; USB1 rearrangements; USB1 susceptibility variants to myeloid malignancies; myelodysplastic syndrome