Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (22)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Lagerstedt, K.
Right arrow Articles by Bondeson, M. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lagerstedt, K.
Right arrow Articles by Bondeson, M. L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Human Molecular Genetics Pages 627-633

Double-strand breaks may initiate the inversion mutation causing the Hunter syndrome
Introduction
Results
   Isolation and sequencing of proximal and distal inversion breakpoints
   Identification of a 1 kb hot-spot region
   Improved diagnosis of Hunter patients with inversions
Discussion
   A hot-spot for recombination located in Xq28
   The inversion mutation is probably initiated by a double-strand break
Materials And Methods
   Preparation of genomic DNA and PCR amplification
   DNA sequencing
Acknowledgements
Abbreviations
References

Double-strand breaks may initiate the inversion mutation causing the Hunter syndrome

Double-strand breaks may initiate the inversion mutation causing the Hunter syndrome Kristina Lagerstedt, Stanislav L. Karsten, Britt-Marie Carlberg, Wim J. Kleijer1, Tönne Tönnesen2, Ulf Pettersson and Marie-Louise Bondeson*

Beijer Laboratory, Department of Medical Genetics, Uppsala University, Box 589, S-751 23Uppsala,Sweden,1Department of Clinical Genetics, University Hospital, Erasmus University, PO Box 1738, 3000 DRRotterdam,The Netherlands and2Department of Biochemistry and Molecular Genetics, The John F. Kennedy Institute, 7 Gl. Landevej, DK-2600Glostrup,Denmark

Received January 1, 1997;Revised and Accepted January 31, 1997DDBJ/EMBL/GenBank accession nos U77685-U77696

We have previously shown that patients with the Hunter syndrome frequently have suffered from a recombination event between the IDS gene and its putative pseudogene, IDS-2, resulting in an inversion of the intervening DNA. The inversion, which might be the consequence of an intrachromosomal mispairing, is caused by homologous recombination between sequences located in intron 7 of the IDS gene and sequences located distal of exon 3 in IDS-2. In order to gain insight into the mechanisms causing the inversion, we have isolated both inversion junctions in six unrelated patients. DNA sequence analysis of the junctions showed that all recombinations have taken place within a 1 kb region where the sequence identity is >98%. An interesting finding was the identification of regions with alternating IDS gene and IDS-2 sequences present at one inversion junction, suggesting that the recombination event has been initiated by a double-strand break in intron 7 of the IDS gene. The results from this study suggest that homologous recombination in man could be explained by mechanisms similar to those described forSaccharomyces cerevisiae. The results also have practical implications for diagnosis of patients with the Hunter syndrome.

INTRODUCTION

Hunter syndrome (or mucopolysaccharidosis type II, MPS-II) is an X-linked recessive disorder, with an incidence of ~1 in 132 000 live male births (1 ). The disorder is caused by a deficiency in the enzyme iduronate-2-sulfatase (IDS) resulting in accumulation of large amounts of heparan and dermatan sulfate in the lysosomes and progressive damage of various tissues and organs. Patients with Hunter syndrome present a broad spectrum of clinical phenotypes ranging from mild to severe forms (2 ).

The IDS locus has been physically mapped to the Xq27.3-q28 boundary. The gene spans a region of ~24 kb, and 10 exons have been identified within this region (3 -5 ). In addition to the IDS gene, a putative pseudogene (IDS-2) has been discovered, which is located 20 kb distal to the functional gene (6 ,7 ). This region contains sequences that are homologous to exons 2, 3 and introns 2, 3 and 7 of the IDS gene, and is located in the opposite orientation compared to the IDS gene. The IDS-2 locus which spans ~3 kb shows an overall >88% homology with the IDS-gene (7 ).

The IDS deficiency in patients with the Hunter syndrome is caused by several different mutations such as point mutations, small deletions and insertions. In ~20% of the patients examined, major structural aberrations such as deletions of the entire gene or rearrangements have been observed (8 ). We have previously shown that in ~13% of patients with Hunter syndrome there has been a recombination event between the IDS gene and the IDS-2, resulting in a disruption of the IDS gene in intron 7 and an inversion of the intervening DNA (9 ). Analysis at the molecular level showed that recombination had occurred within 1.6 kb homologous sequences present in intron 7 of the IDS gene and distal of exon 3 in the IDS-2 locus in six unrelated individuals, suggesting that the homologous regions present in the IDS gene and IDS-2 are hot-spots of recombination. Interestingly, a similar mechanism seems to cause inversions of the factor VIII gene, also located at the long arm of the X chromosome, leading to the severe hemophilia A (10 ,11 ). It has been suggested that these inversions arise by inappropriate intrachromosomal recombinations in male germ cells (9 -12 ).

Most of our current knowledge about homologous recombination originates from studies of prokaryotes, fungi and from transfections of different recombination substrates in mammalian cells. However, studies of germ line events in mammalian cells have been hampered by the lack of suitable experimental systems, and are therefore less well understood. Studying the consequences of homologous recombination in human genes may contribute to our understanding of these events. In order to gain insight into the mechanisms by which the inversions have been generated, we have isolated and sequenced the inversion junctions in six unrelated patients with the Hunter syndrome.

The results from the sequencing suggest that double-strand breaks (DSBs) have initiated the homologous recombination, resulting in an inversion of the intervening DNA. We also present a new PCR amplification assay for improved diagnosis of patients with the inversion mutation.

RESULTS

Isolation and sequencing of proximal and distal inversion breakpoints

The homologous sequences involved in recombination start ~1.9 kb upstream of exon 8 in the IDS gene and 491 bp downstream of exon 3 in the IDS-2 locus and span a region of 1.6 kb (9 ).

The inversion junctions were amplified by PCR on genomic DNA from the patients using the primers IDS814, IDS-99201 or the primers IDS8R, IDS3L-JS, BIDS813 and IDS8rev3. The locations of the primers used are indicated in Figure1 . PCR products containing the distal (1.7 kb) and proximal (2.8 and 1.6 kb) junctions (Fig.1 ), were sequenced and compared with the IDS intron 7 sequence or the corresponding sequence located in the IDS-2 locus.


Figure 1.Gene structure and organisation of the IDS gene, the IDS-2 locus and genes located adjacent to IDS-2 in Xq27.3-q28. The striped boxes show the homologous sequences. The organisation of the genes in normal individuals is shown at the top (6,7 and GenBank accession number U66082). At the bottom the result of homologous recombination is illustrated, with disruption of the IDS gene and the IDS-2 locus and an inversion of the intervening region.

Identification of a 1 kb hot-spot region

The overall sequence identity between the 1.6 kb homologous regions present in the IDS gene and IDS-2 is ~96% (9 ). The differences in sequence within the two regions were used as markers to map the junctions in the different patients. To ascertain that the observed mismatches did not represent polymorphisms 20 X-chromosomes were sequenced within this region. A few polymorphic sites were identified after DNA sequence analysis as shown in Figure2 . The presence of a polymorphic site in intron 7 and the IDS-2 at position 1011, made this mismatch unusable as a marker for mapping of the exchange regions.


Figure 2. Schematic diagram of the DNA sequence of the proximal and distal inversion junctions in six unrelated patients. The differences between the two sequences are shown above with the numbers of the positions as denoted in (7). The detected polymorphisms are indicated by /. The six patients are represented by different lines. Sequences corresponding to intron 7 are marked with black boxes, and corresponding sequences of the IDS-2 locus are shown by white boxes. Due to the homology between these two sequences the exchanges have been assigned to regions between two mismatches, illustrated by grey boxes. When the region corresponding to intron 7 or IDS-2 only is defined by one basepair, for instance distal breakpoint patient I position 591, this region has been magnified to be visible. The detected polymorphisms located in this region were in a few cases excluded from the mismatch pattern when delineating the region where the recombination has occurred. This could be demonstrated by patient II in the distal junction, where differences at the positions 405, 600 and 1011 were ignored when illustrating the mismatch pattern.

The results from the DNA sequence analysis of the PCR products containing the recombination junction from the patients are shown in Figure2 . In all six patients analysed recombinations have occurred within the 1.6 kb region that is homologous between the IDS gene and IDS-2. No deletions or insertions of additional sequences were observed in the regions analysed. Since the homologous regions contain long stretches of sequence identity it was only possible, in most cases, to determine the position of strand exchange at a resolution of less than a few hundred basepairs.

As shown in Figure2 , two different types were identified when analysing the proximal junctions. In the first type, represented by patients I, II and III, the recombinations have occurred between position 854 and 1331. In the second type recombinations have occurred between position 628 and 854. This type is represented by patients IV, V and VI. The proximal junction of patient VI has already been reported (9 ).

The distal junctions showed a different pattern. In at least three patients (I, III and VI) alternating IDS gene and IDS-2 sequences were found at the site of the junction. This is best described in patient I. The distal junction in this patient shows sequence similarity to both the intron 7 and IDS-2 in an alternating pattern within a 368 basepair long region, from position 260 to 628 (Fig.2 ).

Due to the presence of a polymorphic site in the IDS-2 region, at position 405, and the lack of additional markers within this region, it cannot be excluded that the remaining patients (II, IV and V) also have the same pattern of alternating sequences from the IDS gene and the IDS-2 locus.

A comparison of the proximal- and distal recombination junctions within the same patient showed that the exchange regions were unique in five of the six patients analysed. This result suggests that the mutation does not represent a founder effect.

The DNA sequence analysis showed that in all patients recombination has occurred within a region of 1 kb, from position 260 to 1331 in Figure2 , implying that this region is a hot-spot for recombination.

Improved diagnosis of Hunter patients with inversions

Based on the results from this study we have designed two new sets of primers that may be used for diagnosis of Hunter patients with the inversion mutation (Table1 ). The primers are located in the homologous regions present in the IDS gene and the IDS-2 locus but outside the hot-spot region (Fig.1 ). PCR amplifications of the junction boundaries of the six patients included in this study are shown in Figure3 .


Figure 3. PCR amplification of proximal- and distal inversion junctions in six unrelated patients with the Hunter syndrome using new sets of primers. The sequences of the primers are shown in Table 1. Lanes 1, 3, 5 and 12: Amplification of genomic DNA from a normal control. Lanes 2, 4, 6-11 and 13-18: PCR amplification of genomic DNA from patients with an inversion mutation of the IDS gene. Lanes 1 and 2: PCR amplification with primers specific for the IDS-2 locus. Lanes 3 and 4: PCR amplification with primers specific for intron 7. The PCR amplification of proximal inversion junctions are shown in lanes 6-11 and the distal inversion junctions in 13-18. A 100 bp ladder was used as marker (M).

DISCUSSION

A hot-spot for recombination located in Xq28

Genetic recombination is the molecular process by which new combinations of genetic material are generated. Recent identification of recombination protein homologs in yeast and higher eukaryotes suggest that recombination mechanisms are also conserved between prokaryotes and eukaryotes (13 ,14 ).

Homologous recombination plays an important role during meiosis to ascertain proper chromosome segregation through homologue pairing. Homologous recombination can result in equal recombination where break and rejoining of chromosomes occur at the same position, but recombination can also result in deletions or duplications due to imperfect alignment of homologous regions. This type of homologous unequal recombination has been described as the cause of many human disorders (10 ,11 ,15 -17 ) and has also been shown to be involved in X-Y translocations (18 -21 ). In several of these reports recombination has involved repetitive sequences (16 ,17 ). There are also two examples, the IDS gene and the factor VIII gene, where homologous recombination results in inversions (9 -11 ). Both these genes are located on the long arm of the X-chromosome and also share the feature of having repeated regions that are located in an opposite direction compared to the gene. The inversions are most likely caused by inappropriate intrachromosomal recombination during the male meiosis (12 ).

Here we have shown that the homologous recombination between the IDS gene and IDS-2 has occurred at different sites within the same region in the unrelated patients. This result implies that the inversion mutation does not represent a founder effect but rather results from separate recombination events. We have also identified a 1 kb region that comprises a hot-spot for the recombination. This hot-spot region exhibits significantly higher sequence identity (>98%) than the overall >88% homology between the IDS gene and the IDS-2 locus. These data are consistent with previous findings that homologous recombination in humans and other mammals occurs with increased frequency between two homologous regions as the identity increases between them (22 ). Our data also supports previous findings that the homologous recombination preferentially initiates within regions of sequence identity and that branch migration proceeds until a region of divergence is reached at which a resolution of the interacting molecules occurs.

The inversion mutation is probably initiated by a double-strand break

Another interesting observation gained from the sequencing of the inversion junctions is the alternating pattern of sequences from the IDS gene and IDS-2 found in one end of the inversion in at least three of the patients. The alternating pattern of sequences might be caused by conversion events that often are found associated with crossover both in fungi and bacteria (23 ). The conversion events could be explained as the consequence of repair of double-strand gaps or as mismatch repair of heteroduplexes formed between the interacting strands (23 ). The phenomenon of nonrandom distribution of conversions observed here has also been found in fungi. The polarity might be observed as a gradient in conversion frequency where markers located near one end of the gene convert more often than those located in the middle or at the other end of the gene (23 ).

Table 1. Sequence of oligonucleotides used for PCR amplification of the inversion junctions in this study
Name

 Sequence

 Junction amplified
IDS814

 5'-ATATATGGAGGTGCCATAATT-3'

 Distal
IDS-99201

 5'-AACCAAAGACACCAAAAACTG-3'

  
60033-F

 5'-CTCTCCCTGAGCTCATCATTC-3'

 Distal
98855-B

 5'-AACCAACACAACCCTTCATGTTG-3'

  
BIDS813

 5'-GTGTGGCCAGCATTGCTGTTG-3'

 Proximal
IDS8rev3

 5'-ACAGGCTGGGAACCCTGAAA-3'

  
IDS8R

 5'-ATCTAGAATTCAGGTGATCTTACTGTCAAGC-3'

 Proximal
IDS3L-JS

 5'-CTGTGGCGATGCTTACCTCT-3'

  
97690-F

 5'-CCTCTGGGCATGGGATTTAACA-3'

 Proximal
58740-B

 5'-ATCTTCGTTGATTTTTAAGACATA-3'

  
The primers 60033-F/58740-B and 97690-F/98855-B are specific for amplification of the intron 7 and the IDS-2 locus respectively.

From studies inSaccharomyces cerevisiae it has been suggested that all meiotic recombination events are initiated by double-strand breaks (DSB) and transient DSBs have been observed at positions known as recombination hot-spots early in meiosis I prophase (24 ). Recent findings, based on transfection with recombination substrates, suggest that homologous recombination is strongly promoted by the presence of DSBs also in mammalian cells (25 -27 ).

The results from the analysis of the inversion junctions reported here can be explained by a mechanism proposed for homologous recombination involving a DSB as shown in Figure4 .


Figure 4. A model for genetic intrachromosomal recombination caused by a double strand break resulting in an inversion (I) or a gene conversion (II) as shown at the bottom of the figure. An endonuclease initiates the break. Degradation at the ends may leave a free 3' end that can invade a homologous region in the donor DNA. Its 3' end can then be used as a primer for DNA synthesis (indicated by an arrow) resulting in displacement of the donor strand. The DNA molecule that is invaded provides the genetic information needed to repair the double strand break. The model only illustrates four of several possible outcomes. In addition, mismatch correction may occur in regions of heteroduplex DNA where the mismatched basepairs can be repaired in favour of the invading DNA strand or in favour of the resident strand resulting in gene conversion or restoration, respectively.

In the DSB repair model for homologous recombination, an endonuclease initiates the recombination by a break in the DNA duplex (for review see24 ,28 ). The double-strand break is processed by a 5' to 3'-exonuclease leaving single-stranded 3' OH-ends. One 3' OH-end can invade an intact homologous duplex and act as a primer for DNA repair synthesis. As a consequence of this synthesis the other target strand displaced and the formed D loop is enlarged until the other 3' end can anneal to complementary single-stranded sequences. Following gap repair synthesis with the intact strand as template, and branch migration two Holliday junctions are formed. The subsequent cleavage and resolution of the Holliday junctions may generate progeny with crossover or non-crossover, as illustrated in Figure4 by inversion and gene conversion, respectively. In addition, mismatch correction may occur in regions of heteroduplex DNA where the mismatched basepairs can be repaired in favour of the invading DNA strand or in favour of the resident strand (28 ).

Based on findings of alternating sequence homology at the distal inversion junctions (Fig.2 ) we suggest that double-strand breaks have occurred within the intron 7 of the IDS gene and that IDS-2 have acted as a donor strand in these patients.

Inversions, similar to those found in the IDS gene, have been identified in the factor VIII gene, where homologous recombination has occurred between regions in intron 22 and one of two copies of this region, located telomeric of the gene (10 ,11 ). The repeated regions span 9.5 kb in length and have 99.9% identity (29 ). Investigation of the inversion junctions in patients with hemophilia A showed that recombination has occurred without any insertions or deletions between the repeats (29 ). These data are consistent with our findings that the inversions are generated by precise exchange. One interesting observation from the analysis of the inversions in the factor VIII gene is that the recombination between intron 22 and one of the two repeats, three to four times more frequently involves the most telomeric repeat. There is no obvious difference in sequence between the two copies. It has therefore been proposed that the chromosomal location may be of importance (29 ).

From studies inS.cerevisiae it has been suggested that factors such as chromosomal location, specific sequences, chromatin structure and level of transcription influence the meiotic recombination (28 ,30 ) and it has also been shown that features of the chromatin structure play an important role for establishment of meiosis-induced DSB sites (30 ). Furthermore, it has been suggested that sequences, in and around promotors of transcription, are more accessible to enzymes forming DSBs during meiosis and therefore serve as preferential sites for initiation of recombination (30 ). In view of this fact it is worth noting that genes, adjacent to the IDS and IDS-2 loci (Fig.1 ) and both the repeated regions in the factor VIII gene, are expressed in a wide variety of cell types (31 -33 ). One may speculate that the transcriptional activity may alter the chromatin structure by making these regions more accessible to enzymes that form DSBs. This accessibility, in conjunction with the occurrence of repeated regions with high sequence identity, may contribute to the genomic instability observed in the factor VIII and IDS genes. This overall instability could also explain other kinds of alterations within this region, such as deletions due to nonhomologous recombination (S.Karstenet al., in preparation).

It has previously been suggested that these inversion mutations are the results of intrachromosomal recombinations in male germ cells (9 -12 ). Both the factor VIII gene and the IDS gene are located in the distal part of the X chromosome in a region that is generally unpaired in males during meiosis, and this may facilitate an intrachromosomal mispairing between the repeated sequences in these genes. The inverted orientations of the sequences involved in the recombinations in factor VIII and the IDS gene explain why the consequence of the recombinations will result in inversions and not duplications or deletions as normally observed for these kinds of events.

Our results suggest that similar mechanisms to those described forS.cerevisiae might be involved in meiotic recombination in mammalian cells. Further studies of the consequences of recombination in human genes could help us to better understand the mechanisms involved in this process.

MATERIALS AND METHODS

Preparation of genomic DNA and PCR amplification

Genomic DNA was prepared from cultured fibroblasts of the patients or from lymphocytes of normal individuals.

The PCR reactions were carried out in a buffer containing 50 mM KCl, 10 mM TrisHCl pH 8.3, 1.5 mM MgCl2, 200 µM dNTP and 12.5 µg/ml BSA. To this 2 UTaq-polymerase, 1 µM of each primer and ~500 ng genomic DNA were added. The primers used for amplification of the proximal and distal junctions are shown in Table1 . PCR amplification was performed for 35 cycles consisting of a 1 min 94oC denaturing step, a 1 min 60oC annealing step and a 4 min 72oC extension step. For amplification of the distal inversion junctions the samples were run one cycle of 94oC for 7 min prior to addition of theTaq-polymerase and the cycling reactions.

DNA sequencing

DNA sequence analyses were performed on PCR products. All inversion junctions were sequenced at least two times on material from different PCR reactions to verify the obtained sequence.

Sequencing was done by using ABI PRISMtm Dye terminator cycle sequencing core kit, FS (Applied Biosystems division of Perkin Elmer). The sequencing reactions were performed according to the manufacturer's instructions. The reactions were analysed on an ABI 373A DNA Sequencer.

Programs from the Genetics Computer Group (GCG) program package were used to analyse the results. The sequences were compared with the IDS genomic sequence (accession no. L43581) using the Seqed and Bestfit programs from the above mentioned package.

The GenBank accession numbers for the sequences described in this study are U77685-U77696.

ACKNOWLEDGEMENTS

We are grateful to Dr Karin Carlsson and Dr Santanu Dasgupta at the Department of Microbiology, and Dr Hans Ronne at the Department of Medical Immunology and Microbiology, Uppsala University for stimulating discussions during the preparation of this manuscript. Financial support for this project was provided by grants from the Swedish Medical Research Council, the Beijer Foundation and the Marcus Borgström Foundation.

ABBREVIATIONS

DSB, double-strand break; IDS, iduronate-2-sulfatase; IDS-2, iduronate-2-sulfatase pseudogene; MPS II, Mucopolysaccharidosis II; PCR, polymerase chain reaction.

REFERENCES

1 Young,I.D and Harper,P.S. (1982) Incidence of Hunters's syndrome. Hum. Genet., 60, 391-392. MEDLINE Abstract

2 Neufeld,E.F. and Muenzer,J. (1995). In The Metabolic basis of Inherited Disease, C.R. Scriver, A.L. Beaudet, W.E. Sly and D. Valle (eds) Mc Graw-Hill, New York, pp 2465-2494.

3 Flomen,R.H., Green,E.P., Green,P.M., Bentley,D.R. and Giannelli,F. (1993) Determination of the organisation of coding sequences within the iduronate sulphate sulphatase (IDS) gene. Hum. Mol. Genet., 2, 5-10. MEDLINE Abstract

4 Wilson,P.J., Meaney,C.A., Hopwood,J.J. and Morris,C.P. (1993) Sequence of the human iduronate-2-sulphatase (IDS) gene. Genomics 17, 773-775. MEDLINE Abstract

5 Malmgren,H., Carlberg,B-M., Pettersson,U. and Bondeson,M-L. (1995) Identification of an alternative transcript from the human iduronate-2-sulfatase (IDS) gene. Genomics, 29, 291-293. MEDLINE Abstract

6 Bondeson,M-L., Malmgren,H., Dahl,N., Carlberg,B-M. and Pettersson,U. (1995) The presence of an IDS-related locus (IDS-2) in Xq28 complicates the mutational analysis of the Hunter syndrome. Eur. J. Hum. Genet., 3, 219-227.

7 Timms,K.M., Lu,F., Shen,Y., Pierson,C.A., Muzny,D.M., Gu,Y., Nelson,D.L. and Gibbs,R.A. (1995) 130 kb of DNA sequence reveals two new genes and a regional duplication distal to the human iduronate-2-sulfate sulfatase locus. Genome Res., 5, 71-78. MEDLINE Abstract

8 Hopwood,J.J., Bunge,S., Morris,C.P., Wilson,P.J., Steglich,C., Beck,M., Schwinger,E. and Gal,A. (1993) Molecular basis of mucopolysaccharidosis type II: Mutations in the iduronate-2-sulfatase gene. Hum. Mutat., 2, 435-442. MEDLINE Abstract

9 Bondeson,M-L., Dahl,N., Malmgren,H., Kleijer,W.J., Tönnesen,T. Carlberg,B-M. and Pettersson,U. (1995). Inversion of the IDS gene resulting from recombination with IDS-related sequences is a common cause of the Hunter syndrome. Hum. Mol. Genet., 4, 615-621.

10 Lakich,D., Kazazian Jr,H.H., Antonarakis,S.E. and Gitschier,J. (1993) Inversions disrupting the factor VIII gene are a common cause of severe haemophilia A. Nature Genet., 5, 236-241. MEDLINE Abstract

11 Naylor,J., Brinke,A., Hassock,S., Green,P.M. and Giannelli,F. (1993) Characteristic mRNA abnormality found in half the patients with severe haemophilia A is due to large DNA inversions. Hum. Mol. Genet., 2, 1773-1778. MEDLINE Abstract

12 Rossiter,J.P., Young,M., Kimberland,M.L., Hutter,P., Ketterling,R.P., Gitschier,J., Horst,J., Morris,M.A., Schaid,D.J., de Moerloose,P., Sommer,S.S., Kazazian Jr,H.H. and Antonarakis,S.E. (1994) Factor VIII gene inversions causing severe hemophilia A originate almost exclusively in male germ cells. Hum. Mol. Genet., 3, 1035-1039. MEDLINE Abstract

13 Shinohara,A., Ogawa,H., Matsuda,Y., Ushio,N., Ikeo,K. and Ogawa,T. (1993) Cloning of human, mouse and fission yeast recombination genes homologous to RAD51 and recA. Nature Genet., 4, 239-243. MEDLINE Abstract

14 Ellis,N.A., Groden,J., Ye,T.Z., Straughen,J., Lennon,D.J., Ciocci,S., Proytcheva,M. and German,J. (1995) The Bloom's syndrome gene product is homologous to RecQ helicases. Cell, 83, 655-666. MEDLINE Abstract

15 Vnencak-Jones,C.L. and Phillips III,J.A. (1990) Hot spots for growth hormone gene deletions in homologus regions outside of Alu repeats. Science, 250, 1745-1748. MEDLINE Abstract

16 Hu,X. and Worton,R.G. (1992) Partial gene duplication as a cause of human disease. Hum. Mutat., 1, 3-12. MEDLINE Abstract

17 Ketterling,R.P., Ricke,D.O., Wurster,M.W. and Sommer,S.S. (1993) Deletions with inversions: report of a mutation and review of the literature. Hum. Mutat., 2, 53-57. MEDLINE Abstract

18 Rouyer,F., Simmer,M.C., Page,D.C. and Weissenbach,J. (1987) A sex chromosome rearrangement in a human XX male caused by Alu-Alu recombination. Cell, 51, 417-425. MEDLINE Abstract

19 Yen,P.H., Tsai,S-P., Wenger,S.L., Steele,M.W., Mohandas,T.K. and Shapiro,L.J. (1991) X/Y translocations resulting from recombination between homologous sequences on Xp and Yq. Proc. Natl. Acad. Sci. USA, 88, 8944-8948. MEDLINE Abstract

20 Guioli,S., Incerti,B., Zanaria,E., Bardoni,B., Franco,B., Taylor,K., Ballabio,A. and Camerino,G. (1992) Kallmann syndrome due to a translocation resulting in an X/Y fusion gene. Nature Genet., 1, 337-340. MEDLINE Abstract

21 Weil,D., Wang,I., Dietrich,A., Poustka,A., Weissenbach,J. and Petit,C. (1994) Highly homologous loci on the X and Y chromosomes are hot-spots for ectopic recombinations leading to XX maleness. Nature Genet., 7, 414-419. MEDLINE Abstract

22 Metzenberg,A.B., Wurzer,G., Huisman,T.H.J. and Smithies,O. (1991) Homology requirements for unequal crossing over in humans. Genetics, 128, 143-161. MEDLINE Abstract

23 Hastings,P.J. (1988) In Genetic Recombination. American Society for Microbiology, Washington DC, pp 397-428.

24 Shinohara,A. and Ogawa,T. (1995) Homologous recombination and the roles of double-strand breaks. Trends Biochem. Sci., 20, 387-391. MEDLINE Abstract

25 Subramani,S. and Seaton,B.L. (1988) In Genetic Recombination. American Society for Microbiology, Washington DC, pp. 549-573.

26 Rouet,P., Smih,F. and Jasin,M. (1994) Expression of a site-specific endonuclease stimulates homologous recombination in mammalian cells. Proc. Natl. Acad. Sci. USA, 91, 6064-6068. MEDLINE Abstract

27 Smih,F., Rouet,P., Romanienko,P.J. and Jasin,M. (1995) Double-strand breaks at the target locus stimulate gene targeting in embryonic stem cells. Nucleic Acids Res., 23, 5012-5019. MEDLINE Abstract

28 Haber,J.E. (1992) Exploring the pathways of homologous recombination. Curr. Opin. Cell. Biol. 4, 401-412. MEDLINE Abstract

29 Naylor,J.A., Buck,D., Green,P., Williamson,H., Bentley,D. and Giannelli,F. (1995) Investigation of the factor VIII intron 22 repeated region (int22h) and the associated inversion junctions. Hum. Mol. Genet., 4, 1217-1224. MEDLINE Abstract

30 Wu,T-C. and Lichten,M. (1994) Meiosis-induced double-strand break sites determined by yeast chromatin structure. Science, 263, 515-518.

31 Levinson,B., Kenwrick,S., Lakich,D., Hammonds Jr,G. and Gitschier,J. (1990) A transcribed gene in an intron of the human factor VIII gene. Genomics, 7, 1-11. MEDLINE Abstract

32 Levinson,B., Kenwrick,S., Gamel,P., Fisher,K. and Gitschier,J. (1992) Evidence for a third transcript from the human factor VIII gene. Genomics, 14, 585-589. MEDLINE Abstract

33 Timms,K.M., Bondeson,M-L., Ansari-Lari,M.A., Lagerstedt,K., Munzy,D.M., Dugan-Rocha,S.P., Nelson,D.L., Pettersson,U. and Gibbs,R.A. (1997) Molecular and phenotypic variation in patients with severe Hunter syndrome. Hum. Mol. Genet., 479-486.

*To whom correspondence should be addressed

This page is maintained by OUP admin. Last updated Thu Mar 13 17:29:21 GMT 1997. Part of the OUP Journals World Wide Web service.Copyright Oxford University Press, 1996


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Cold Spring Harb Symp Quant BiolHome page
P. STANKIEWICZ, K. INOUE, W. BI, K. WALZ, S.-S. PARK, N. KUROTAKI, C.J. SHAW, P. FONSECA, J. YAN, J.A. LEE, et al.
Genomic Disorders: Genome Architecture Results in Susceptibility to DNA Rearrangements Causing Common Human Traits
Cold Spring Harb Symp Quant Biol, January 1, 2003; 68(0): 445 - 454.
[Abstract] [PDF]

Home page
 Hum Mol GenetHome page
S. Aradhya, T. Bardaro, P. Galgoczy, T. Yamagata, T. Esposito, H. Patlan, A. Ciccodicola, A. Munnich, S. Kenwrick, M. Platzer, et al.
Multiple pathogenic and benign genomic rearrangements occur at a 35 kb duplication involving the NEMO and LAGE2 genes
Hum. Mol. Genet., October 1, 2001; 10(22): 2557 - 2567.
[Abstract] [Full Text] [PDF]

Home page
 Genome ResHome page
M. A. Pujana, M. Nadal, M. Gratacòs, B. Peral, K. Csiszar, R. González-Sarmiento, L. Sumoy, and X. Estivill
Additional Complexity on Human Chromosome 15q: Identification of a Set of Newly Recognized Duplicons (LCR15) on 15q11-q13, 15q24, and 15q26
Genome Res., January 1, 2001; 11(1): 98 - 111.
[Abstract] [Full Text]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (22)
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Lagerstedt, K.
Right arrow Articles by Bondeson, M. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Lagerstedt, K.
Right arrow Articles by Bondeson, M. L.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?