Linked Ichthyosis and the STS Gene at Xp223

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 3^-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(GST), 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 additional 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

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 ANEMO pseudogene. Open arrowheads depict the large inverted repeats that contain the 3' portion of NEMO and the LAGE2 (solid arrow) genes. The recombination products involving the various pairs of repeats are shown. The drawings are not to scale.

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 ANEMO pseudogene. Open arrowheads depict the large inverted repeats that contain the 3' portion of NEMO and the LAGE2 (solid arrow) genes. The recombination 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 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).

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