Polymorphism and hemophilia A causing inversions in distal Xq28: a complex picture

Bagnall, Richard D.; Giannelli, F.; Green, Peter

doi:10.1111/j.1538-7836.2005.01566.x

Cited by 33 publications

(45 citation statements)

References 8 publications

(12 reference statements)

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“…Recently, int22h-1 and int22h-2 sequences were reported to display the same orientation, 17 which may cause, theoretically, highly deleterious 0.5 Mb deletions or duplications in the case of recombination between misaligned sister chromatids or homologous chromosomes. It has been suggested that they are either extremely rare or nonexistent 13,18,19 and could cause problems in mutation testing in HA. 20 However, a very recent The size of amplicons corresponds to the sum of the distance between primer pairs and the length of the tail added to the locus-specific primer pairs for PCR amplification (30 bp in total).…”

Section: Discussionmentioning

confidence: 99%

Intron 22 homologous regions are implicated in exons 1–22 duplications of the F8 gene

et al. 2013

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The intron 22 inversion found in up to 50% of severe hemophilia A patients results from a recombination between three intron 22 homologous copies (int22h). This study evaluated the implication of these copies in the formation of extended duplications comprising exons 1-22 of the factor 8 (F8) gene and their association with hemophilia and mental retardation. Two hemophilic patients with moderate and severe phenotypes and a third nonhemophilic patient with developmental delay were studied. All exhibited a duplication of F8 gene exons 1-22 identified by multiplex ligation-dependent probe amplification along with abnormal patterns on Southern blotting and unexpected long-range PCR amplification. Breakpoint analysis using array comparative genomic hybridization was performed to delimit the extent of these rearrangements. These duplications were bounded on one side by the F8 intragenic int22h-1 repeat and on the other side by extragenic int22h-2 or int22h-3 copies. However, the simultaneous identification of a second duplication containing F8 gene exons 2-14 for the moderate patient and the classical intron 22 inversion for the severe patient are considered in this study as the genetic causal defects of hemophilia. This study shows that the well-known int22h copies are involved in extended duplications comprising F8 gene exons 1-22. These specific duplications are probably not responsible for hemophilia and intellectual disability, but should be carefully considered in genetic counseling, while continuing to investigate the causal mutation of hemophilia.

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Section: Discussionmentioning

confidence: 99%

Intron 22 homologous regions are implicated in exons 1–22 duplications of the F8 gene

et al. 2013

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“…1E), who is expected to carry already the recently proposed polymorphic, nonpathogenic inversion (step 1 in Fig. 2) as a prerequisite for the int22h2-related inversion (Bagnall et al, 2005). Figure 1.…”

Section: Resultsmentioning

confidence: 69%

“…Such complex rearrangements are probably facilitated by the higher flexibility of the telomeric end of the X chromosome in the absence of a second pairing X-chromosome during male meiosis (Rossiter et al, 1994). Grey boxes indicate the homologous regions flanking the extragenic copies int22h2 and int22h3 that facilitate intragenic homologous recombination resulting in a polymorphic, non-pathogenic inversion (step 1) with int22h2 consequently located distal and in opposite orientation to int22h1 (Bagnall et al, 2005). The proposed formation and stabilization of a loop structure by inverted repeat elements (Alu and LINE, represented by triangles indicating the orientation) allowed templating of the MPP1 fragment insertion in F8 intron 15 (step 2).…”

Section: Resultsmentioning

confidence: 99%

Recurrent inversion with concomitant deletion and insertion events in the coagulation factor VIII gene suggests a new mechanism for X-chromosomal rearrangements causing hemophilia A

et al. 2007

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Recurrent int22h-related inversions in the coagulation factor VIII gene (F8) are the most common cause of severe hemophilia A. Such inversions have repeatedly been hypothesized to be associated with concomitant deletions that are responsible for an increased risk of immune responses against therapeutic exogenous factor VIII. However, exact DNA breakpoints have not yet been reported. In a patient with persistent factor VIII-inactivating antibodies, molecular analysis of F8 including Southern Blot, long-range PCR and primer walking techniques revealed a combination of an int22h2-related inversion, deletion of exons 16-22 and insertion of a duplicated part of the X-chromosomal MPP1 gene. This novel genomic rearrangement was also detectable in the patient's mother, but absent in both maternal grandparents. The genetic defect most likely originated from a complex Xchromosomal recombination event during spermatogenesis due to the formation of a DNA loop stabilized by Alu and LINE repeat elements. Elucidation of such combined mutations may allow early identification of patients at high risk of developing factor VIII-neutralizing antibodies and will help to understand the mechanisms behind gross chromosomal rearrangements causing hemophilia A and other diseases.

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“…This means that only one of the repeats should participate in F8 inversion events, but both types of inversion are known. This observation led to the suggestion of an inversion polymorphism that involved the two distal repeats [33,34] and which has subsequently been verified (Figure 2) [35]. The frequency of the two alleles in the population might explain the long-standing mystery of why one of the distal repeats is far more frequently involved in inversions than the other.…”

Section: Genomic Disordersmentioning

confidence: 93%

“…int22h-1 lies in intron 22 of the F8 gene, whereas int22h-2 and int22h-3 lie within the arms of a large inverted repeat, which are separated by a $70 kb spacer (thin black line). (a) and (b) represent alleles that differ as a result of an inversion, possibly created by nonallelic homologous recombination between the arms of this repeat [33].…”

Section: Complex Disordersmentioning

confidence: 99%

The sequences of the human sex chromosomes

Ross

Tyler‐Smith

2006

Current Opinion in Genetics & Development

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Polymorphism and hemophilia A causing inversions in distal Xq28: a complex picture

Cited by 33 publications

References 8 publications

Intron 22 homologous regions are implicated in exons 1–22 duplications of the F8 gene

Intron 22 homologous regions are implicated in exons 1–22 duplications of the F8 gene

Recurrent inversion with concomitant deletion and insertion events in the coagulation factor VIII gene suggests a new mechanism for X-chromosomal rearrangements causing hemophilia A

The sequences of the human sex chromosomes

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