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    Hemophilia B (HB) is a hereditary bleeding disorder caused by the genetic variation of the coagulation factor IX (FIX) gene (F9). Several F9 structural abnormalities, including large deletion and/or insertion, have been observed to cause HB development. However, there is limited information available on F9 deep intronic variations. In this study, we report about a novel large deletion/insertion observed in a deep region of F9 intron 1 that causes mRNA splicing abnormalities. The patient was a Japanese male diagnosed with moderate HB (FIX:C = 3.0 IU/dL). The genomic DNA of the patient was isolated from peripheral blood leukocytes. DNA sequences of F9 exons and splice donor/acceptor sites were analyzed via polymerase chain reaction and Sanger sequencing. Variant-affected F9 mRNA aberration and FIX protein production, secretion, and coagulant activity were analyzed by cell-based exon trap and splicing-competent FIX expression vector systems. A 28-bp deletion/476-bp insertion was identified in the F9 intron 1 of a patient with moderate HB. A DNA sequence identical to a part of the inverted HNRNPA1 exon 12 was inserted. Cell-based transcript analysis revealed that this large intronic deletion/insertion disrupted F9 mRNA splicing pattern, resulting in reduction of protein-coding F9 mRNA. A novel deep intronic F9 rearrangement was identified in a Japanese patient with moderate HB. Abnormal F9 mRNA splicing pattern due to this deep intronic structural variation resulted in a reduction of protein-coding F9 mRNA, which probably caused the moderate HB phenotype. Copyright © 2022 Elsevier Ltd. All rights reserved.


    Koya Odaira, Fumika Kawashima, Shogo Tamura, Nobuaki Suzuki, Mahiru Tokoro, Yuri Hayakawa, Atsuo Suzuki, Takeshi Kanematsu, Shuichi Okamoto, Akira Takagi, Akira Katsumi, Tadashi Matsushita, Midori Shima, Keiji Nogami, Tetsuhito Kojima, Fumihiko Hayakawa. F9 mRNA splicing aberration due to a deep Intronic structural variation in a patient with moderate hemophilia B. Thrombosis research. 2022 May;213:91-96

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    PMID: 35313235

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