Genomic Rearrangements Resulting in PLP1 Deletion Occur by Nonhomologous End Joining and Cause Different Dysmyelinating Phenotypes in Males and Females

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Genomic Rearrangements Resulting in PLP1 Deletion Occur by Nonhomologous End Joining and Cause Different Dysmyelinating Phenotypes in Males and Females Ken Inoue, Hitoshi Osaka, Virginia C. Thurston, Joe T.R. Clarke, Akira Yoneyama, Lisa Rosenbarker, Thomas D. Bird, M.E. Hodes, Lisa G. Shaffer, James R. Lupski The American Journal of Human Genetics Volume 71, Issue 4, Pages 838-853 (October 2002) DOI: 10.1086/342728 Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 1 Detection of PLP1 deletion and breakpoint mapping by STS-content mapping and interphase FISH analyses. Map (top) shows selected STS markers surrounding the PLP1 locus that were used in this study. Results of agarose gel electrophoresis of PCR products for each STS-PCR of a normal control are shown below. Probes used in the interphase FISH studies were assigned with corresponding color in the photograph. The green probe, RP1-39B6, was used as an intrachromosomal control. Results for one proband from each family are shown. Interphase FISH using u125A1 that contains the entire PLP1 gene (middle column) revealed no red signal in each patient, whereas interphase FISH using RP1-34H10 and RP1-81E11 (left and right columns) reveal signals for markers proximal and distal to the breakpoints for the deletion, respectively. Accordingly, agarose gel electrophoresis analyses (right column) of STS-content PCR products for each patient revealed no amplification from STSs in the deleted segment, including PLP1 exonic sequences. STS-content-mapping analyses revealed distinct locations for the deletion breakpoints in each family. The American Journal of Human Genetics 2002 71, 838-853DOI: (10.1086/342728) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 2 Southern analysis identified a recombination-specific junction fragment in family HOU542. Genomic DNA from proband (BAB1379; lane 1), mother (BAB1381; lane 2), healthy male sibling (BAB1380; lane 3), normal control (lane 5), and two patients with PLP1 duplication (lanes 5 and 6) were used for genomic Southern hybridization analysis using four different endonucleases. We observed deletion-specific junction fragments (arrowheads) in the patient and mother, but not in other individuals. Bottom, Location of the hybridization probe, u35G3.20K, is shown. The American Journal of Human Genetics 2002 71, 838-853DOI: (10.1086/342728) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 3 Interphase and metaphase FISH of family HOU542 revealed transposition of PLP1 to chromosome 19. A, Interphase FISH using probes for PLP1 (u125A1; red) and an intrachromosomal control (RP1-39B6; green) revealed one PLP1 signal (arrowhead) appearing distant from the control signal in the mother (BAB1381). B, In the same individual, metaphase FISH using chromosome 19-specific probe (green) localized one copy of PLP1 (red) on 19qtel (arrowhead). The small box shows an enlarged image of derivative chromosome 19. C, Interphase FISH of the healthy brother (BAB1380) revealed that he also has the derivative chromosome 19 with PLP1 signal (arrowhead). D, An ideogram representing insertional translocation of PLP1 from Xq22.2 to 19qtel (red). Green signals indicate intrachromosomal controls that were used in FISH analyses. The American Journal of Human Genetics 2002 71, 838-853DOI: (10.1086/342728) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 4 Results of interphase FISH and haplotype analyses of family HOU669. A pedigree of the family HOU669 is shown, with haplotypes at DXS8096, CA-PLP, DXS1191, and DXS8075, as well as interphase FISH images using both PLP1 (red) and control (green) probes. The healthy sister and mother carry a deleted chromosome shown by both FISH and haplotype analyses. Neither of the maternal grandparents revealed deletion by FISH. The haplotype analysis shows that the deletion chromosome (light yellow boxes) was derived from the grandfather. The American Journal of Human Genetics 2002 71, 838-853DOI: (10.1086/342728) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 5 STS-content PCR and junction-specific PCR analyses. Flanking genomic regions of the proximal and distal breakpoints are shown for each family. Interspersed repeats are marked. In each region, the centromere is to the left and the telomere to the right. Recombination breakpoints and flanking sequence are shown as thick arrows. Light gray bars represent the position of the target regions for STS-content PCR, and the corresponding agarose gel photographs are presented. In each experiment, results for a proband (P) and a normal control (C) are shown. Note that STS within the deleted genomic region resulted in no amplification in probands. Results of the agarose gel electrophoresis for junction-specific PCR analyses (right) revealed amplification from patients and carriers, but not from noncarriers or normal control. Breakpoint PCR for family PMD1 showed PCR amplification in all three individuals (two patients and one carrier mother) as well as in a normal control, using primers flanking the recombination breakpoint, suggesting the existence of contiguous wild-type sequence of this region. We used BAB1379 as a negative control to determine the specificity of this PCR assay. The American Journal of Human Genetics 2002 71, 838-853DOI: (10.1086/342728) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 6 DNA sequence of recombination junction fragments. DNA sequence for each deletion-specific junction fragment obtained by DOP-PCR was perfectly aligned to the wild-type flanking finished genomic sequences for both proximal and distal breakpoints. Alignments with the proximal boundary were shaded in light gray, and those with the distal boundary were shaded in dark gray. Top, Sequence alignment in family HOU542. The recombination breakpoint was embedded in an 18-bp stretch of perfect sequence alignment (shaded in black with white letters). Middle, Sequence alignment in family HOU669. The recombination breakpoint was located within a 12-bp segment that has partial sequence identity to proximal boundary sequence (underlined). The origin of this 12-bp segment is unknown. Bottom, Sequence alignment in family PMD1. The sequences of the junction fragment consist of three segments (see fig. 5). In addition to the proximal and distal boundaries, a 34-bp middle fragment is shown in black shading. This middle segment has 2-bp overlaps with proximal and distal segments, respectively (asterisks above the alignment). The American Journal of Human Genetics 2002 71, 838-853DOI: (10.1086/342728) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 7 STS-content mapping of the deletion intervals in the genomic physical map of the Xq22.2 region. The top rectangles represent chromosomal bands, and the solid horizontal line below shows physical distances from the telomeric end of the short arm (left). The light blue rectangle below displays STR (blue) and STS (black) markers in this region. The light yellow rectangle represents genes (red) and predicted genes (black) in this region. Blue bars indicate a contig of large-insert genomic bacterial clones (BACs, PACs, and cosmids) that were sequenced and annotated by the draft Human Genome Sequencing project. The contig was obtained from the Ensembl genome browser. Annotation of each gene was determined on the basis of the Ensembl genome database project and additional computational analyses of each gene. Two LCRs, LCR-PMDA and LCR-PMDB, are shown (green arrows). Thick horizontal bars and intermediate thin lines indicate the deleted genomic segment in each family, determined by the STS-content mapping of deletion segments using STS markers in this region (arrowheads). The dotted line in family PMD1 represents the deleted genomic region estimated by STS-content mapping, whereas solid lines show the actual genomic rearrangements identified by junction-fragment sequence analysis. The result of each PCR experiment is shown as a plus (+) or a minus (−) symbol. A red rectangle in family PMD1 indicates the location of the 5-Kb probe used in the interphase FISH analysis. The American Journal of Human Genetics 2002 71, 838-853DOI: (10.1086/342728) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 8 Genomic structure of LCR-PMDA and LCR-PMDB. A, Flanking the gap in the draft genome sequence, two inverted repeats, LCR-PMDA and LCR-PMDB, span 45 Kb and 32 Kb, respectively. LCR-PMDA has an inset of a 13-Kb genomic segment that is abundant in interspersed repeat elements (>94%). Each LCR consists of two homologous segments, designated A1a and A2 for LCR-PMDA, as well as A1b and A3 for LCR-PMDB. B, Sequence identity analysis among the segments, using BLAST2. Segments A1a and A1b reveal the highest identity, whereas A2 and A3 show the lowest identity. C, Phylogenic tree shows evolution of each segment in LCR-PMDA and LCR-PMDB, based on the sequence identity and genomic structure. The American Journal of Human Genetics 2002 71, 838-853DOI: (10.1086/342728) Copyright © 2002 The American Society of Human Genetics Terms and Conditions