A mutation in the 3' untranslated region of the factor IX gene in four families with hemophilia B

Vielhaber, Erica; Jacobson, David P.; Ketterling, Rhett P.; Liu, Jing Zhong; Sommer, Steve S.

doi:10.1093/hmg/2.8.1309

Cited by 22 publications

(17 citation statements)

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“…The 3' UTR of the gene has recently been cloned. A minor hot spot for mutation occurs in the 3' UTR of the haemophilia B gene (Vielhaber et al, 1993). In myotonic dystrophy, an unstable trinucleotide repeat in the 3' UTR of the gene is prone to expansion in patients.…”

Section: Difficulty In Mutation Detectionmentioning

confidence: 99%

Molecular basis of neurofibromatosis type 1 (NF1): Mutation analysis and polymorphisms in the NF1 gene

Upadhyaya¹,

Shaw²,

Harper³

1994

Hum. Mutat.

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Neurobromatosis type 1 (NF1) is one of the commonest genetic disorders in humans. The gene for NF1 was cloned in 1990. The protein encoded by the gene (neurofibromin) has extensive sequence homology with GTPase-activating protein (GAP). Despite screening the whole coding region of the gene for large and medium size rearrangements and approximately 40% of the coding region of the gene for small alterations, only 45 germ-line mutations have been reported in more than 500 unrelated patients. Of these, 25 mutations involve small changes in the gene, of which 17 (68%) result in the formation of an inappropriate stop codon. A "hot spot" for mutations has not been identified. The high mutation rate at this locus and the general difficulty in identifying mutations are discussed. A complete understanding of the structure and function of the NF1 gene awaits further detailed studies of both naturally occurring and in vitro-generated mutations.

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Section: Difficulty In Mutation Detectionmentioning

confidence: 99%

Molecular basis of neurofibromatosis type 1 (NF1): Mutation analysis and polymorphisms in the NF1 gene

Upadhyaya¹,

Shaw²,

Harper³

1994

Hum. Mutat.

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“…In 1993 a 3'UTR variant (Chr.X, NC_000023.11:g.139563228A>G) was described in four families with moderate to severe hemophilia B [6]. Affected individuals showed FIX activity between <1 and 4.5% of normal.…”

Section: Introductionmentioning

confidence: 99%

“…At present, the FIX mutation database lists 21 patients from different geographic regions with this variant (http://www.factorix.org; [7,8]; S1 Table). The variant may generate a 5' splice site (5'SS) by an A to G transition at position +1157 downstream of the stop codon (c.2545A>G; NM_000133) in the 3' UTR [6]. However, the underlying pathophysiological mechanism remained unsolved.…”

Section: Introductionmentioning

confidence: 99%

Pathological mechanism and antisense oligonucleotide-mediated rescue of a non-coding variant suppressing factor 9 RNA biogenesis leading to hemophilia B

et al. 2020

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Loss-of-function mutations in the human coagulation factor 9 (F9) gene lead to hemophilia B. Here, we dissected the consequences and the pathomechanism of a non-coding mutation (c.2545A>G) in the F9 3' untranslated region. Using wild type and mutant factor IX (FIX) minigenes we revealed that the mutation leads to reduced F9 mRNA and FIX protein levels and to lower coagulation activity of cell culture supernatants. The phenotype could not be compensated by increased transcription. The pathomechanism comprises the de novo creation of a binding site for the spliceosomal component U1snRNP, which is able to suppress the nearby F9 poly(A) site. This second, splicing-independent function of U1snRNP was discovered previously and blockade of U1snRNP restored mutant F9 mRNA expression. In addition, we explored the vice versa approach and masked the mutation by antisense oligonucleotides resulting in significantly increased F9 mRNA expression and coagulation activity. This treatment may transform the moderate/severe hemophilia B into a mild or subclinical form in the patients. This antisense based strategy is applicable to other mutations in untranslated regions creating deleterious binding sites for cellular proteins.

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“…It has previously been reported that sequence variation in the 3'-UTR is associated with transcriptional modifications, splicing, or mRNA stability [12, 13]. In 5 families with hemophilia B (HB), a point mutation in the 3'-UTR of the F9 gene greatly reduced plasma FIX concentration to less than 3% of the normal level [14]. In addition, a 653-bp deletion located in the 3'-UTR of the F9 gene was found to be responsible for mild HB [15].…”

Section: Discussionmentioning

confidence: 99%

Identification of a sharedF8mutation in the Korean patients with acquired hemophilia A

et al. 2011

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Although uncommon, acquired hemophilia A (HA) is associated with a high rate of mortality due to severe bleeding. In spite of many hypotheses regarding the cause of acquired HA, there is as yet no established theory. In this study, we investigated the possibility that mutation(s) in the F8 gene may be correlated with the development of inhibitory autoantibodies. Direct sequencing analysis was performed on all 26 exons of the F8 gene of 2 patients exhibiting acquired HA. Both patients were found to share a common point mutation (c.8899G>A) in the 3'-untranslated region (3'-UTR) of exon 26. This is the first report on the genotyping of F8 in the context of acquired HA.

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A mutation in the 3' untranslated region of the factor IX gene in four families with hemophilia B

Cited by 22 publications

References 0 publications

Molecular basis of neurofibromatosis type 1 (NF1): Mutation analysis and polymorphisms in the NF1 gene

Molecular basis of neurofibromatosis type 1 (NF1): Mutation analysis and polymorphisms in the NF1 gene

Pathological mechanism and antisense oligonucleotide-mediated rescue of a non-coding variant suppressing factor 9 RNA biogenesis leading to hemophilia B

Identification of a sharedF8mutation in the Korean patients with acquired hemophilia A

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