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

Abstract

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.

Disease onset in X-linked dystonia-parkinsonism correlates with expansion of a hexameric repeat within an SVA retrotransposon inTAF1

“…Their composite structure consists of (5′–3′) hexameric CCCTCT repeats, two antisense Alu-like fragments, a variable number of GC-rich tandem repeats (VNTR), sequences from the env gene of a human endogenous retrovirus (HERV), and a poly(A) tail ( 30 ). At least 85 human diseases are currently linked to active retroelements, with at least 12 associated specifically with SVAs ( 28 , 34 – 45 ). These SVA insertions have been associated with various types of transcriptional interference, which may be due to their capacities to activate cryptic splice sites, generate transcripts via intrinsic promoter activity, and form G-quadruplex (G4) structures that inhibit the progression of RNA polymerase II (RNAP II) ( 32 , 46 – 54 ).…”

A Homozygous Ancestral SVA-Insertion-Mediated Deletion in WDR66 Induces Multiple Morphological Abnormalities of the Sperm Flagellum and Male Infertility

“…44 The spectrum of diseases that have been reported in relation to SVA transposition, including Marfan syndrome, hemophilia B, neurofibromatosis types 1 and 2, leukemia, and congenital muscular dystrophy, has been increasing progressively. [45][46][47][48][49][50] In this study, we report a homozygous CNV that is generated by an SVA transposition event and causes MMAF, leading to male infertility.…”

Potential impact of primate-specific SVA retrotransposons during the evolution of human cognitive function

“…4,16 SVAs can also induce alternative splicing and exon skipping which can result in the generation of alternative transcripts of a gene as documented by disease causing insertions. [17][18][19] Thus SVA insertions may generate new interactions between what would otherwise be distinct pathways. 8,20 In this communication, we suggest a more global involvement of genes associated with SVA insertions in CNS-relevant pathways.…”