Molecular Analysis of a Constitutional X-Autosome Translocation in a Female with Muscular Dystrophy

Bodrug, Sharon; Ray, P. N.; Gonzalez, IL; Schmickel, Roy D.; Sylvester, James E.; Worton, R G

doi:10.1126/science.3629260

Cited by 67 publications

(28 citation statements)

References 32 publications

(7 reference statements)

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“…Short direct repeats distinct from S, pentamers may also increase the likelihood for c-myc/IgHa rearrangements. In this respect, the excess of short recombinogenic motifs in the 5' region of c-myc such as the tetrameric sequences GAGG (13,25), CCCT (26), CGGC (27), and the pentameric GC stretches CGCGG/CCGCC (refs. 28 and 29; Fig.…”

Section: Discussionmentioning

confidence: 99%

Detection of recombinations between c-myc and immunoglobulin switch alpha in murine plasma cell tumors and preneoplastic lesions by polymerase chain reaction.

Janz

Müller

Shaughnessy

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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Virtually all murine plasmacytomas carry chromosomal translocations that activate c-myc. The predominant (=90%) c-myc-activating chromosomal translocation in pristane (2,6,10,14-tetramethylpentadecane)-induced plasmacytomas in BALB/c mice is a reciprocal translocation t(12;15) in which an immunoglobulin heavy-chain switch sequence is joined to the 5' region of c-myc. The most common switch region involved is S.. We developed a direct PCR method to screen for recombinations between c-myc and S.. The critical step in establishing the method was the cloning and sequencing of the 5' flank of Ca, a region with a reduced number of switch repeats that is much more favorable for designing specific PCR primers than the highly repetitive S. region. In applying this PCR method, we detected translocation-specific junction fragments in transplanted (10/16, 63%) and primary (5/15, 33%) plasmacytomas. Moreover, the sensitivity of a nested version of that technique allowed us to discern rare t(12;15)s in BALB/c mice in the preneoplastic stage of plasmacytomagenesis (8/20 mice, 40%) as early as 30 days after administration of pristane. We conclude that t(12;15) is the probable primary, if not initiating, oncogenic step in plasmacytomagenesis.Plasmacytomas (PCTs) induced in BALB/cAnPt mice by the intraperitoneal (i.p.) injection of pristane (2,6,10,14-tetramethylpentadecane) (1) carry reciprocal chromosomal translocations t(12;15), t(6;15), or t(15;16) that are associated with the activation of the c-myc protooncogene (2). In the t(12;15) which occurs in 90% ofthe tumors the near 5' flanking region, the first exon or part of the first intron of c-myc is disrupted and joined head to head with genes in the immunoglobulin heavy chain (IgH) gene complex (3-6). The most common immunoglobulin gene breakpoint is in either the a-chain switch (Sa) region (7) The goal of the present study was to take advantage of these common breaksites in Sa/S'-Ca and devise a PCR method for detecting illegitimate-i.e., nonhomologous-recombinations between Sa/5'-Ca and c-myc. We describe here a direct PCR technique that detects 63% (10/16) of all translocation breakpoints in transplanted PCTs that are known to involve the Sa/5'-Ca,, region. We have applied this methodology to detect similar translocations in primary tumors and in the very early preneoplastic stages of PCT development.

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Section: Discussionmentioning

confidence: 99%

Detection of recombinations between c-myc and immunoglobulin switch alpha in murine plasma cell tumors and preneoplastic lesions by polymerase chain reaction.

Janz

Müller

Shaughnessy

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

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“…However, the mechanisms generating these translocations are largely unknown and in only a few cases is the nucleotide sequence information of the translocation junctions available. One involves the translocation of rRNA genes on chromosome 21 to the short arm of the X chromosome interrupting the Duchenne muscular dystrophy locus (48). This translocation is reciprocal but a small amount of DNA is missing.…”

Section: Resultsmentioning

confidence: 99%

X/Y translocations resulting from recombination between homologous sequences on Xp and Yq.

Yen

Tsai

Wenger

et al. 1991

Proc. Natl. Acad. Sci. U.S.A.

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Several regions of sequence homology between the human X and Y chromosomes have been identified. These segments are thought to represent areas of these chromosomes that have engaged in ineiotic recombination in relatively recent evolutionary times. Normally, the X and Y chromosomes pair during mdosis and exchange DNA only within the pseudoautosomal region at the distal short arms of both chromosomes. However, it has been suggested that aberrant recombination involving other segments of high homology could be responsible for the production of X/Y translocations. We have studied four X/Y translocation patients using molecular probes detecting homologous sequences on X and Y chromosomes. In one translocation the breakpoints have been isolated and sequenced. The mapping data are consistent with the hypothesis that X/Y translocations arise by homologous recombination. The sequencing data from one translocation demonstrate this directly.The mammalian sex chromosomes are thought to have evolved from an ancestral homologous chromosome pair (1). Although sequences have been deleted, inserted, or rearranged on the sex chromosomes over time to accommodate their now specialized functions, significant sequence similarities remain between the present-day X and Y chromosomes. Sequences in the pseudoautosomal region at the terminal portions of the short arms of the sex chromosomes are identical and, during male meiosis, there is a single and obligatory X-Y crossover within this region (2). Occasionally the X-Y interchange occurs outside the pseudoautosomal region and the testis-determining factor (TDF) gene is transferred to the X chromosome resulting in an XX male phenotype (3, 4). Outside the pseudoautosomal region, homologous sequences have been found on the long arm of the X chromosome and the short arm or the proximal long arm of the Y chromosome. These regions share >95% similarity as detected by probes DXYS1, DXYS61, and others (5-10). Because some of these sequences are found only on the X chromosome of great apes, they are thought to have been generated by transposition of sequences from the X chromosome to the Y chromosome after the divergence of humans from great apes; however, recent loss of the Y homologs in great apes is also a possible explanation. In addition, several loci in the Xpter-Xp22 region were found to share 85-95% similarity with sequences in Yqll or the pericentric region of the Y chromosome. These include the genes for steroid sulfatase (STS; refs. 11 and 12), the tooth enamel protein amelogenin (AMG; ref. 13), and several loci defined by anonymous DNA fragments (14,15). The homology shared by the short arm of the X chromosome and the long arm of the Y chromosome has been cited as evidence for a pericen-

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“…Structural abnormalities of the X-chromosome are well-known causes of selective, nonrandom inactivation. In case of a balanced reciprocal X; autosome translocation, the normal X is usually inactivated, and this presumably minimizes interruption of gene expression by chromosomal rearrangements (Bodrug et al, 1987). The third possi- bility is deletion or mutation of that gene on both X chromosomes (Guo et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Hunter disease in a girl caused by R468Q mutation in the iduronate-2-sulfatase gene and skewed inactivation of the X chromosome carrying the normal allele

et al. 1997

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Molecular Analysis of a Constitutional X-Autosome Translocation in a Female with Muscular Dystrophy

Cited by 67 publications

References 32 publications

Detection of recombinations between c-myc and immunoglobulin switch alpha in murine plasma cell tumors and preneoplastic lesions by polymerase chain reaction.

Detection of recombinations between c-myc and immunoglobulin switch alpha in murine plasma cell tumors and preneoplastic lesions by polymerase chain reaction.

X/Y translocations resulting from recombination between homologous sequences on Xp and Yq.

Hunter disease in a girl caused by R468Q mutation in the iduronate-2-sulfatase gene and skewed inactivation of the X chromosome carrying the normal allele

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