Female haemophiliac homozygous for the factor VIII intron 22 inversion mutation, with transcriptional inactivation of one of the factor VIII alleles

Dávid, Dezső; Moráis, Sara; Ventura, Célia; Campos, M.

doi:10.1046/j.1365-2516.2003.00704.x

Cited by 21 publications

(24 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The paternally derived X‐chromosome from the patient had been preferentially inactivated in more than 95% of her somatic cells. A similar case of a female with two inversions was reported by David and co‐workers [5]. These investigators found transcriptional inactivation of the maternal F8 allele.…”

Section: Discussionsupporting

confidence: 75%

Severe haemophilia A in a female resulting from an inherited gross deletion and a de novo codon deletion in the F8 gene

et al. 2008

View full text Add to dashboard Cite

Haemophillia A (HA) is an X-linked bleeding disorder caused by mutations in the F8 gene. While the disease affects 1 in 5000 males, phenotypic expression of haemophilia A is rare in females, similar to other X-linked recessive disorders. We describe a 5-year-old female with severe haemophilia A. We determined the underlying molecular defect in the F8 genes of the proband and her closest family members by direct DNA sequencing, marker analysis and quantitative real-time polymerase chain reaction. The patient showed two different mutations in the F8 gene: the paternal copy of the F8 gene had a de novo p.Phe652/653 deletion in exon 13 while the maternally inherited gene showed a large deletion encompassing exons 1 to 22. The structural analysis of residues Phe652/Phe653 based on a three-dimensional model of activated factor VIII provides evidence of the impact of the mutant factor VIII protein in the clinical manifestations of the patient. This unusual finding highlights the need to perform a thorough molecular analysis including sequencing, marker and quantitative analyses to identify compound heterozygous females with HA.

show abstract

Section: Discussionsupporting

confidence: 75%

Severe haemophilia A in a female resulting from an inherited gross deletion and a de novo codon deletion in the F8 gene

et al. 2008

View full text Add to dashboard Cite

show abstract

“…The phenotypic expression of haemophilia in females is a rare event. The commonest cause of female haemophilia is the non‐random inactivation of normal X‐chromosome [32] followed by homozygosity of haemophilic mutations [33], monosomy for X‐chromosome or a gross structural defect such as a deletion or translocation [34]. In this report, we identified a Thr2253Pro novel amino acid change and an intron 22 inversion in the homozygous state in two female haemophiliacs.…”

Section: Discussionmentioning

confidence: 92%

Identification of factor VIII gene mutations in 101 patients with haemophilia A: mutation analysis by inversion screening and multiplex PCR and CSGE and molecular modelling of 10 novel missense substitutions

Jayandharan¹,

Shaji²,

Baidya

et al. 2005

Haemophilia

View full text Add to dashboard Cite

Haemophilia A (HA) is an X-linked bleeding disorder caused by diverse mutations in the human coagulation factor VIII (FVIII) gene. We have analysed DNA from 109 unrelated Indian patients with HA for their FVIII gene defects. Among these patients 89 (82%) had severe (FVIII:C <1%) HA, 11 (10%) had moderate (FVIII:C 1-5%) HA and nine (8%) had mild (FVIII:C 5-30%) HA. These patients were first screened for the common intron 22 and intron 1 inversions. Inversion negative samples were screened for point mutations by a multiplex PCR and conformation sensitive gel electrophoresis strategy. Mutations were identified in 101 of the 109 patients. These included two (2%) intron 1 and 51 (51%) intron 22 inversions, four (4%) gross deletions and 44 (43%) point mutations. Twenty-nine novel causative mutations, including 11 missense, seven frameshift, five nonsense mutations, three splice site defects and three gross deletions were detected. Ten of the novel missense mutations were studied by molecular modelling. Two different (Thr2253Pro and Pro1392fs) mutations were seen in four unrelated families and FVIII gene haplotyping suggested a common founder effect. Seven of these 109 patients had inhibitors. Among them, four had intron 22 inversions, one had a novel gross deletion (delexon 2-9) and one a nonsense mutation (Trp1535Stop). In one of these patients, no mutation could be identified in the FVIII gene. A Thr2253Pro novel mutation and an intron 22 inversion were identified in two female haemophiliacs. The data from this study suggests that the spectrum of gene defects in Indian patients with HA is as heterogeneous as reported in other populations.

show abstract

“…It is interesting to note that the female patient studied had slightly more serious FVIII deficiency and clinical symptoms than her father. The skewed X‐chromosome inactivation, which occurs in some HA carriers [12,13] and occasionally female patients [14], may be one possible mechanism for the phenomenon. However, an approximately 50% reduction of FVIII:Ag and FVIII:C in the patient compared with her father supported the theory that both of the F8 alleles were expressed equally.…”

Section: Discussionmentioning

confidence: 99%

Female hemophilia A heterozygous for a de novo frameshift and a novel missense mutation of factor VIII

Cai

Wang

Dai

et al. 2006

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

. Female hemophilia A heterozygous for a de novo frameshift and a novel missense mutation of factor VIII. J Thromb Haemost 2006; 4: 1969-74. Summary. Background: Hemophilia A (HA) is an X-chromosome-linked recessive disorder. Aim: We report the case of a female HA patient with a moderate decrease of factor (F) VIII activity and antigen (FVIII:C 3.4%, FVIII:Ag 4.2%) and severe bleeding symptoms. Methods: The patient's father had mild FVIII deficiency (FVIII:C 6.9%, FVIII:Ag 7.4%), and her mother had normal FVIII activity. The von Willebrand disease antigen and von Willebrand factor ristocetin cofactor activity were normal in all family members. The genomic DNA was extracted from the peripheral blood lymphocytes of the patient and her family members. Long-distance polymerase chain reaction (PCR) was employed to screen for the intron 22 inversion of the FVIII coding gene (F8). The F8 coding sequence was amplified with PCR and sequenced with an automatic sequencer. Results: Two heterozygous mutations were identified in the patient: one a substitution of nucleotide 5981T by C that leads to a missense mutation Leu1975Pro, and the other an insertion of an ÔAÕ between nucleotides 3637 and 3638 (3637_3638insA) that shifts the reading frame and predicts a premature stop codon downward. The mutation Leu1975Pro was identified in the father's F8; however, 3637_3638insA was a de novo mutation that occurred in the patient's maternalderived F8. Real-time PCR was applied to analyze the level of ectopically F8 gene transcripts in the peripheral lymphocytes of family members. The ectopic transcripts of F8 of the patient were less abundant than the normal control (patient:normal control ratio 0.67), whereas her parents showed no significant difference from the normal control. Conclusion: The FVIII deficiency of the HA patient resulted from a de novo occurrence of a frameshift 3637_3638insA in her maternal-derived F8 and a novel missense mutation Leu1975Pro inherited from her father.

show abstract

Female haemophiliac homozygous for the factor VIII intron 22 inversion mutation, with transcriptional inactivation of one of the factor VIII alleles

Cited by 21 publications

References 17 publications

Severe haemophilia A in a female resulting from an inherited gross deletion and a de novo codon deletion in the F8 gene

Severe haemophilia A in a female resulting from an inherited gross deletion and a de novo codon deletion in the F8 gene

Identification of factor VIII gene mutations in 101 patients with haemophilia A: mutation analysis by inversion screening and multiplex PCR and CSGE and molecular modelling of 10 novel missense substitutions

Female hemophilia A heterozygous for a de novo frameshift and a novel missense mutation of factor VIII

Contact Info

Product

Resources

About