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17 X Chromosome Rearrangements

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17 X Chromosome Rearrangements Chapter 17 / X Chromosome Rearrangements 247 17 X Chromosome Rearrangements Pauline H. Yen, PhD CONTENTS BACKGROUND INTRODUCTION DELETIONS/DUPLICATIONS CAUSED BY NAHR BETWEEN DIRECT LCRS INVERSIONS CAUSED BY NAHR BETWEEN INVERTED LCRS DELETIONS/DUPLICATIONS CAUSED BY NHEJ THE SHOX GENE DELETIONS CONTIGUOUS GENE SYNDROMES SUMMARY REFERENCES BACKGROUND X chromosome rearrangements usually convey clinical manifestations in the hemizygous males and are, thus, readily ascertained. They are found in all parts of the X chromosome and are associated with more than 20 disorders. Some of the rearrangements are the results of homologous recombination between low-copy repeats (LCRs) on the X chromosome or between large homologous regions on the X and Y chromosome, whereas others are caused by nonhomologous end-joining (NHEJ). For most large deletions associated with contiguous gene syndromes, the deletion breakpoints remain uncharacterized. The deletions, as well as inversions and duplications on the X chromosome, occur mainly in male germ cells, indicating intrachromatid or sister chromatid exchange as the underlying mechanism. INTRODUCTION Among all human chromosomes, the X chromosome seems to have more than its share of genomic disorders identified so far (1). There are two main reasons for the apparent prevalence of genomic disorders on the X chromosome. The hemizygous status of the X chromosome in males allows phenotypic manifestation of rare recessive genomic disorders that would have escaped detection if they were present on an autosome. In addition, high homology shared between the X and the Y chromosome makes the X chromosome specifically prone to X/Y translocation, resulting in the deletion of the terminal sequences (2). To date, more than 20 genomic disorders have been identified on the X chromosome. Deletions associated with the genomic disorders can be easily detected in the males by polymerase chain reaction or Southern From: Genomic Disorders: The Genomic Basis of Disease Edited by: J. R. Lupski and P. Stankiewicz © Humana Press, Totowa, NJ 247 248 Part IV / Genomic Rearrangements and Disease Traits blotting, whereas the carrier status of a female is usually determined by fluorescence in situ hybridization (FISH) analysis (3–6). In this chapter, X-linked genomic disorders are grouped according to the underlying mechanisms such as nonallelic homologous recombination (NAHR) between direct LCRs, NAHR between inverted LCRs, and NHEJ. For most of the Short Stature Homeobox (SHOX) deletions and contiguous gene syndromes, the breakpoints have not been characterized and, thus, the mechanisms remain unclear. DELETIONS/DUPLICATIONS CAUSED BY NAHR BETWEEN DIRECT LCRS Most cases of X-linked ichthyosis (XLI), color blindness, and incontinential pigmenti (IP) are caused by recurrent deletions resulting from NAHR between direct LCRs (7–9). In XLI the LCRs flank the steroid sulfatase (STS) gene, in color blindness the color pigment genes reside within the LCRs, and in IP the LCRs are one within and one outside the nuclear factor (NF)-κB essential modulator (NEMO) gene. When NAHR occurs between two direct repeats on the same chromatid, it generates only deletion (Fig. 1A). If the recombination involves two X chromosome homologs or sister chromatids, it generates both duplication and deletion (Fig. 1A). Reciprocal duplications have been identified at the color pigment gene cluster and the NEMO locus (8,10). Although duplications at the STS locus have also been reported, whether they involve the same LCRs as the recurrent deletion remains to be determined (11). Studies on de novo NEMO deletions in IP patients show that most cases occur in the paternal germ cells, indicating unequal crossover between sister chromatids or intrachromatid recombination as the underlying mechanism (9). X-Linked Ichthyosis and the STS Gene at Xp22.3 XLI (MIM 308100) affects approx 1 in 5000 males worldwide (12). It is caused by a deficiency of the microsomal enzyme steroid sulfatase (STS) that hydrolyzes a variety of 3β- hydroxysteroid sulfates. The STS gene at Xp22.3 consists of 10 exons and spans approx 135 kb of genomic DNA (13). There is a truncated STS pseudogene at Yq11 that contains sequences homologous to five of the exons. XLI is one of the first genomic disorders found to have recurrent deletions flanked by LCR elements (7). Up to 90% of XLI patients have the entire STS gene deleted (14). The deletions are heterogeneous in size and the breakpoints spread over several megabases. A majority of the deletions have common breakpoints within two direct LCRs, S232A and S232B, that are 1.6 Mb apart (Fig. 1B). The common recurrent 1.6-Mb deletion is present in approx 87% of STS deletion patients in the Unites States and Japan, and 30% of the patient population in Mexico (15–18). One-third of the Mexican patients appear to have a smaller recurrent deletion with the distal breakpoint at S232A and the proximal breakpoint somewhere between S232B and another LCR G1.3 (DXF22S1) (18). The 1.6-Mb segment between S232A and S232B contains four genes, HDHD1A(GS1), PNPLA4(GS2), VCX-8r/VCX-A, and LOC392425 in addition to STS (19–21). Interestingly, patients with the 1.6-Mb deletion have the same phenotype as those with mutations within the STS gene, indicating that removal of the addi- tional genes around STS has no apparent phenotypic consequences. There are six copies of S232 repeats within the human genome, four at Xp22.3 flanking STS and two at Yq11. The X-linked S232 repeats are highly polymorphic in length. They span more than 2 Mb and are oriented in different directions (Fig. 1B). The 1.6-Mb deletion breakpoints Chapter 17 / X Chromosome Rearrangements 249 Fig. 1. Nonallelic homologous recombination (NAHR) between direct low-copy repeats. Horizontal arrows depict genes in the 5' to 3' direction and arrowheads depict repeats. (A) Models of NAHR. Recombination between repeats on different chromatids produces both deletion and duplication, whereas recombination between repeats on the same chromatid produces only deletion. (B) The steroid sulfatase (STS) gene and its flanking S232 repeats. The solid arrows within the arrowheads represent the Variable Charge X genes within the S232 repeats. Vertical arrows connect the repeats that are involved in the NAHR to generate the STS deletion. (C) Tandem array of the color pigment genes. Only one green color pigment (GCP) gene in addition to the red color pigment gene is shown. Recombination between the intergenic regions (rearrangement 1) changes the copy number of the GCP gene in the recombinant chromosomes. Recombination between the genes (rearrangement 2) results in hybrid genes in addition to changed gene copy number. (D) Complex structure of the NEMO/LAGE region. Gray unlabeled arrowheads depict the int3h repeats that are present in introns 3 and the 3' flanking regions of NEMO (depicted as open arrow) as well as the truncated ΔNEMO pseudogene. Open arrowheads depict the large inverted repeats that contain the 3' portion of NEMO and the LAGE2 (solid arrow) genes. The recom- bination products involving the various pairs of repeats are shown. The drawings are not to scale. fall within S232A and S232B, which are in the same direction and share more than 11 kb of 95% identity. The structure of the S232 repeats is quite complex. Each S232 repeat contains 5 kb of unique sequence in addition to two elements, RU1 and RU2, that are composed of variable number of tandem repeats (22). The repeating unit of RU2 is of highly asymmetric sequence and in itself contains a variable number of a GGGA repeat. The size of RU2 varies from 0.6 kb to more than 23 kb among different individuals, accounting entirely for the observed polymorphism at the S232 loci. RU1 consists of a 30-bp repeat unit and is a part of a testis-specific gene, Variable Charge X (VCX) or Variable Charge Y (VCY), that is complete 250 Part IV / Genomic Rearrangements and Disease Traits embedded in the S232 repeat (21). The VCX/Y family encodes basic proteins that appear to play a role in the regulation of ribosome assembly during spermatogenesis (23). The RU2 VNTR sequences as well as the open chromatin structure associated with active transcription of the VCX genes may facilitate homologous recombination between S232A and S232B, though the exact locations of the deletion breakpoints within the S232 repeats have not been determined (22,24). Color Blindness and the Red and Green Pigment Genes at Xq28 Color blindness affects approx 5% of the male population worldwide, and a vast majority of the cases are caused by defects in the color pigment genes on the X chromosome (8). Of the genes encoding the three color pigments in humans, the blue pigment gene is located on chromosome 7, and the red pigment (Opsin 1 Long-wave-sensitive, OPN1LW) and green pigment (Opsin 1 Middle-wave-sensitive, OPN1MW) genes are embedded in head-to-tail tandem-arrayed repeating units at Xq28. Such tandem arrangement predisposes the red and green pigment genes to NAHR and genomic rearrangement. The pigment genes consist of six exons spanning 14 kb. They are derived from a duplication event 30 million years ago and share 98% similarity throughout the entire gene. The repeating unit in the tandem array includes a single pigment gene at the 5' end and 25 kb of intergenic sequences. The red pigment gene is located at the 5' end of the array, followed by one or more copies of the green pigment gene (Fig. 1C). Unequal crossover within the 25-kb intergenic regions would generate X chromo- somes with increased or decreased copies of the green pigment gene (Fig. 1C1). This accounts for the variable copy number of the green pigment gene in the human population. Of the X chromosomes in the normal population with trichromatic vision, the percentages carrying one, two, three, four, and more copies of the green pigment gene are 25, 50, 20, and 5%, respectively.
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