SVA retrotransposition in exon 6 of the coagulation factor IX gene causing severe hemophilia B

Hemophilia B is an X-linked recessive bleeding disorder caused by abnormalities of the coagulation factor IX gene ( F9 ). Insertion mutations in F9 ranging from a few to more than 100 base pairs account for only a few percent of all hemophilia B cases. We investigated F9 to elucidate genetic abnorma...

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Bibliographic Details
Published in:International journal of hematology 2015-07, Vol.102 (1), p.134-139
Main Authors: Nakamura, Yuki, Murata, Moe, Takagi, Yuki, Kozuka, Toshihiro, Nakata, Yukiko, Hasebe, Ryo, Takagi, Akira, Kitazawa, Jun-ichi, Shima, Midori, Kojima, Tetsuhito
Format: Article
Language:English
Subjects:
Alternative Splicing
Alu Elements
Case Report
Exons
Factor IX - genetics
Genetic Association Studies
Hematology
Hemophilia B - diagnosis
Hemophilia B - genetics
Humans
Infant
Male
Medicine
Medicine & Public Health
Minisatellite Repeats
Oncology
Polymerase Chain Reaction
Retroelements
Severity of Illness Index
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Summary:Hemophilia B is an X-linked recessive bleeding disorder caused by abnormalities of the coagulation factor IX gene ( F9 ). Insertion mutations in F9 ranging from a few to more than 100 base pairs account for only a few percent of all hemophilia B cases. We investigated F9 to elucidate genetic abnormalities causing severe hemophilia B in a Japanese subject. We performed PCR-mediated analysis of F9 and identified a large insertion in exon 6. Next, we carried out direct sequencing of a PCR clone of the whole insert using nested deletion by exonuclease III and S1 nuclease. We identified an approximately 2.5-kb SINE-VNTR-Alu (SVA)-F element flanked by 15-bp duplications in the antisense orientation in exon 6. Additionally, we carried out exontrap analysis to assess the effect of this retrotransposition on mRNA splicing. We observed that regular splicing at exons 5 and 6 of F9 was disturbed by the SVA retrotransposition, suggesting that abnormal FIX mRNA may be reduced by nonsense-mediated mRNA decay. In conclusion, this is the first report of SVA retrotransposition causing severe hemophilia B; only five cases of LINE-1 or Alu retrotranspositions in F9 have been reported previously.
ISSN:0925-5710
1865-3774
DOI:10.1007/s12185-015-1765-5