PMID- 15459970
OWN - NLM
STAT- MEDLINE
DCOM- 20050729
LR  - 20061115
IS  - 1098-1004 (Electronic)
IS  - 1059-7794 (Linking)
VI  - 24
IP  - 5
DP  - 2004 Nov
TI  - Homeologous recombination between AluSx-sequences as a cause of hemophilia.
PG  - 440
AB  - Although large deletions from the coagulation factor VIII gene, F8, are 
      responsible for 5% of severe hemophilia A (seHA), few of them have been fully 
      characterised. A detailed description of a large partial deletion of the F8 
      caused by unequal recombination between homeologous AluSx-derived sequences is 
      presented. The proband, a case of isolated hemophilia A with a high inhibitor 
      titre (5700 BU), showed a consistent absence of PCR-amplification of exons 4 to 
      10, EX4_EX10del. Two approaches were used to narrow down the deletion 
      breakpoints: a direct physical analysis based on PCR (that additionally permits 
      carrier detection in the family); and, under the hypothesis that the mutation 
      resulted from homologous recombination, sequence alignments of F8 intron 3 and 
      10. Both approaches indicate an unequal crossing over (CO) between two 
      Alu-related sequences. Both elements involved were derived from the 
      AluSx-subfamily consensus and demonstrate 86% sequence identity (with only 
      single-base mismatches), with three gaps (of 2, 3 and 14-bases) and two main 
      tracts of perfectly homologous sequence (28 and 24-bp). The short stretch of 
      intron 10 embedded into intron 3 sequence, linked to the CO, represents a typical 
      hallmark of homologous recombination (double-strand break repair model). A 
      detailed description of EX4_EX10del mutation is 
      c.[338+3485delins1687+2223_1687+2225; 338+3551_1687+2291 del]. The common 
      involvement of unequal homologous recombination mediated by repetitive elements 
      allowed us to suggest that our experimental design (based on intron sequence 
      alignments) may be successfully applied to rearrangements involved in other 
      X-linked inherited diseases. Like other Alu-rich genes throughout the human 
      genome, Alu-mediated homologous recombination in F8 may be an important cause of 
      hemophilia by promoting large DNA deletions.
CI  - Copyright 2004 Wiley-Liss, Inc.
FAU - Rossetti, Liliana C
AU  - Rossetti LC
AD  - Instituto de Investigaciones Hematologicas Mariano R. Castex, Academia Nacional 
      de Medicina de Buenos Aires, Argentina. rossetti@hematologia.anm.edu.ar
FAU - Goodeve, Anne
AU  - Goodeve A
FAU - Larripa, Irene B
AU  - Larripa IB
FAU - De Brasi, Carlos D
AU  - De Brasi CD
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hum Mutat
JT  - Human mutation
JID - 9215429
SB  - IM
MH  - Alu Elements/*genetics
MH  - Base Sequence
MH  - Chromosome Breakage/genetics
MH  - Chromosome Deletion
MH  - Consensus Sequence/genetics
MH  - DNA Mutational Analysis
MH  - Exons/genetics
MH  - Genomics
MH  - Hemophilia A/*genetics
MH  - Humans
MH  - Introns/genetics
MH  - Models, Genetic
MH  - Molecular Sequence Data
MH  - Polymerase Chain Reaction
MH  - Recombination, Genetic/*genetics
MH  - Sequence Deletion/genetics
MH  - *Sequence Homology, Nucleic Acid
EDAT- 2004/10/02 05:00
MHDA- 2005/07/30 09:00
CRDT- 2004/10/02 05:00
PHST- 2004/10/02 05:00 [pubmed]
PHST- 2005/07/30 09:00 [medline]
PHST- 2004/10/02 05:00 [entrez]
AID - 10.1002/humu.9288 [doi]
PST - ppublish
SO  - Hum Mutat. 2004 Nov;24(5):440. doi: 10.1002/humu.9288.