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Molecular Definitionof Breakpoints Associatedwith Human Xq

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Molecular Definitionof Breakpoints Associatedwith Human Xq Am. J. Hum. Genet. 58:154-160, 1996 Molecular Definition of Breakpoints Associated with Human Xq Isochromosomes: Implications for Mechanisms of Formation Daynna J. Wolff,' Andrew P. Miller,1 Daniel L. Van Dyke,2 Stuart Schwartz,' and Huntington F. Willard1 'Department of Genetics and Center for Human Genetics, Case Western Reserve University and University Hospitals of Cleveland, Cleveland; and 2Medical Genetics and Birth Defects Center, Henry Ford Hospital, Detroit Summary erated by a misdivision of the centromere, resulting in To test the centromere misdivision model of isochromo- structurally rearranged chromosomes with two mirror- some formation, we have defined the breakpoints of cy- image arms attached to a single centromere. Although togenetically monocentric and dicentric Xq isochromo- this may be a significant mechanism for the formation somes (i(Xq)) from Turner syndrome probands, using of isochromosomes in some plants and insects (e.g., see FISH with cosmids and YACs derived from a contig Darlington 1939; Smith et al. 1950; Fletcher and Hewitt spanning proximal Xp. Seven different pericentromeric 1988), centromere misdivision may be less likely in breakpoints were identified, with 10 of 11 of the i(Xq)s mammals, particularly in humans (Phelan et al. 1988; containing varying amounts of material from Xp. Only Sharp et al. 1990; Shaffer et al. 1991). In human studies, one of the eight cytogenetically monocentric i(Xq)s dem- the term "isochromosome" is generally extended to in- onstrated a single alpha-satellite (DXZ1) signal, consis- clude isodicentrics and monocentrics without genetically tent with classical models involving centromere misdivi- identical arms (Van Dyke 1988). sion. The remaining seven were inconsistent with such The most common isochromosome seen in humans a model and had breakpoints that spanned proximal contains two copies of the long arm of the X chromo- Xpll.21: one was between DXZ1 and the most proxi- some (i(Xq)) (Van Dyke 1988). Large-scale surveys have mal marker, ZXDA; one occurred between the dupli- demonstrated that >,15% of Turner syndrome patients cated genes, ZXDA and ZXDB; two were -2 Mb from contain an i(Xq) in mosaic or nonmosaic form (Palmer DXZ1; two were adjacent to ALAS2 located 3.5 Mb and Reichmann 1976; Hook and Warburton 1983; from DXZ1; and the largest had a breakpoint just distal Ranke et al. 1983; Held et al. 1992), making the isochro- to DXS1013E, indicating the inclusion of 8 Mb of Xp mosome for Xq the most common structural abnormal- DNA between centromeres. The three cytologically di- ity observed in this syndrome. Despite the fact that centric i(Xq)s had breakpoints distal to DXS423E in i(Xq)s are a common cause of the Turner syndrome Xpll.22 and therefore contained -12 Mb of DNA be- phenotype, their molecular basis is unclear. It was recog- tween centromeres. These data demonstrate that the ma- nized 20 years ago that approximately two-thirds of so- jority of breakpoints resulting in i(Xq) formation are in called i(Xq)s were actually dicentric, as determined by band Xpll.2 and not in the centromere itself. Therefore, C-banding (de la Chapelle and Stenstrand 1974; Hsu et we hypothesize that the predominant mechanism of al. 1978); however, data from only a few molecular i(Xq) formation involves sequences in the proximal studies document the presence of X short-arm sequences short arm that are prone to breakage and reunion events in i(Xq) chromosomes (Callen et al. 1987; Harbison et between sister chromatids or homologous X chromo- al. 1988; Sharp et al. 1990; Lorda-Sanchez et al. 1991). somes. In these studies, the cytogenetically dicentric i(Xq)s and one-third of cytogenetically "monocentric" i(Xq)s were shown to include the short-arm sequence DXS14 Introduction (p58.1). Overall, there are quite limited data on the rela- Darlington (1939) originally proposed that isochromo- tive frequency of i(Xq)s with centromeric or proximal somes in the plant Fritillaria kamtschatkensis were gen- Xp breakpoints, and, to date, there are no data on the distribution of Xp breakpoints among different i(Xq)s. Received August 24, 1995; accepted for publication October 16, In order to understand their mechanism of formation 1995. and to test directly the centromere-misdivision model Address for correspondence and reprints: Dr. Huntington F. Wil- of isochromosome formation, we have undertaken the lard, Department of Genetics, Case Western Reserve University, 2109 molecular characterization of 11 i(Xq)s derived from Adelbert Road, Cleveland, OH 44106. from a © 1996 by The American Society of Human Genetics. All rights reserved. patients with Turner syndrome. Using probes 0002-9297/96/5801-0018$02.00 contig spanning the pericentromeric region of Xp 154 Wolff et al.: Definition of i(Xq) Breakpoints 155 Table 1 Isochromosomes Obtained for Study Case (ID) Karyotypea [% of cells] Source 1 (GM02595) 46,X,i(X)(qter-cen-qter) [100] Camden Cell Repository 2 (1275) 46,X,i(Xq) [100] Present study 3 (Y525U) 46,X,i(Xq) [100] R. Breg 4 (TH) 46,X,i(X)(qter-cen-qter) [100] Present study 5 (GM00088) 45,X/46,X,del(X)(pO)/46,X,i(Xq) [7/50/43] Camden Cell Repository 6 (MR) 45,X/46,X,i(Xq) [7/93] Present study 7 (BB) 45,X/46,X,i(Xq) [10/90] L. Shaffer 8 (GM03543) 45,X/46,X,i(X)(qter-cen-qter) [40/60] Camden Cell Repository 9 (B28057) 45,X/46,X,psu dic(X)(pl1.21) [45155] Present study 10 (B22610) 46,X,psu dic(X)(pll.21) [100] Present study 11 (GM00339) 45,X/46,dic(X)(qter-pll::pll-qter) [60/40] Camden Cell Repository a As stated on the referring clinical cytogenetic report. (Miller et al. 1995), we have defined molecularly the were analyzed by use of a BioRad MRC 600 confocal i(Xq) breakpoints in these cases. On the basis of these microscope system (Hercules) with a Zeiss Axioplan mi- data, we hypothesize that the majority of i(Xq)s arise croscope. Initially, probes for ZXDA and DXS423E not by centromere misdivision but via Xp breakage and were used to screen the i(Xq)s. The breakpoint region reunion between sister chromatids or homologous X was then narrowed or expanded by use of additional chromosomes. probes, and an exact location was established on the X chromosome consensus map (Willard et al. 1994) Subjects, Material, and Methods (fig. 1). Subjects and Cell Cultures Results Eleven Turner syndrome probands, whose clinical cy- togenetic analyses revealed a monocentric (cases 1-8) Three i(Xq)s were dicentric or pseudodicentric, on the or dicentric (cases 9-11) i(Xq), were ascertained for basis of the cytogenetic analysis (table 1, cases 9-11). analysis (table 1). Case 9 was analyzed by use of high- In each ofthese cases, two centromeric DXZ1 hybridiza- resolution techniques, whereas the remaining cases were tion signals were clearly distinguishable in metaphase examined by use of routine cytogenetic procedures preparations, with obvious material between the signals (band level -500). Fibroblast cell cultures (cases (e.g., see fig. 2C) (Sharp et al. 1990). The breakpoints GM02595, GM00088, GM00339, and Y525), lym- for these cytogenetically dicentric chromosomes were phoblast cell lines (cases GM03543, TH, MR, and B28051), or fixed cell pellets (cases 1275, B22610, and 0 60 160 Mb BB) were obtained for breakpoint determination. The I -I!I- cell cultures were passaged and harvested, and slides li were prepared according to standard laboratory proce- I dures. Partial data have been presented elsewhere for FIF"In cases GM02595, Y525, and GM00088 (Sharp et al. 52.5 54.5 56.5 58.5 Mb 1990). I I ... I FISH Representative nonchimeric YACs and cosmids were I L ... V I I I I ,07722 selected from a contig spanning the pericentromeric re- or . .: gion of the X chromosome (Miller et al. 1995) (see fig. 1). The location and size of each probe are given in table 2. Probes were labeled with biotin by use of the Bio- Nick kit (BRL) with additional DNase I. Figure 1 Detailed map of Xcen-Xpll.22, with the localized probes that span the region. The map positions and physical distances FISH was performed as described by Miller et al. are based on data from the 1994 International X Chromosome Work- (1995). For each probe, 5-10 metaphases with both the shop (Willard et al. 1994). Full information on the probes used is normal X and the abnormal X chromosomes present given in table 2. 156 Am. J. Hum. Genet. 58:154-160, 1996 Table 2 Probe Information Size Probe Name Probe Type (kb) Locus Cytogenetic Location Map Positiona pBamX7 Plasmid 2 DXZ1 X cen 58.5-61.5 ICRFc100G11100 Cosmid 40 ZXDA Xpl 1.21 58.3 ICRFC10OA07135 Cosmid 40 ZXDB Xpl 1.21 58.1 ICRFY900AO215 YAC 380 DXS579 Xpl 1.21 57.2 ICRFy900H1054 YAC 480 DXS741 Xpl 1.21 56.4 743C10 YAC 1,220 ALAS2 Xpl 1.21 55.0 ICRFy900CO5164 YAC 670 DXS1013E Xpl 1.21 54.5 ICRFc100D02100 Cosmid 40 DXS423E Xpl 1.22 53.4 OATL2-1 YAC 630 OATL2 Xpl1.22 52.5 ICRFy900FO5O1 YAC 480 OATL1 Xpl 1.23 49.0 ICRFc100E0981 Cosmid 40 UBE1 Xpll.3 46.0 a Based on the estimated scale given for the consensus map of the X chromosome, from the report of the fifth international workshop (Willard et al. 1994). localized to Xp11.22 distal to DXS423E (figs. 3 and 4). Case Y525 (Sharp et al. 1990) had a unique pericen- Thus, on the basis of the location of DXS423E on the tromeric structure with a breakpoint between the dupli- X consensus map, these cytogenetically dicentric iso- cated genes, ZXDA (which revealed a double signal) and chromosomes include >12 Mb of short-arm material ZXDB (which was negative), located at position 58 on (>6 Mb of Xp included from each side of the point of the X consensus map (figs.
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