Clustered Organization of Krüppel Zinc-Finger Genes at Xp11.23, Flanking a Translocation Breakpoint at OATL1: A Physical Map with Locus Assignments for ZNF21, ZNF41, ZNF81, and ELK1

doi:10.1006/geno.1994.1240

Genomics

Volume 21, Issue 1, 1 May 1994, Pages 180-187

https://doi.org/10.1006/geno.1994.1240 Get rights and content

Abstract

The ZNF21, ZNF41, and ZNF81 genes encode Krüppel-type zinc-finger proteins (ZFPs) and have previously been mapped to chromosome Xp. Published data describing the clustering of ZFP genes on human autosomes led us to investigate the organization of ZNF21, ZNF41, and ZNF81 on the X chromosome. Rodent-human hybrid analysis sublocalized all three genes to Xp22.11-p11.23. ZNF21, ZNF41, and ZNF81 were then shown to segregate within a series of YACs (95 to 730 kb) containing known markers at Xp11.23, such that these YACs could be assembled into a contig spanning approximately 1.5 Mb of DNA. Southern analysis of intact YACs and YAC DNAs cut with rare-cutter restriction enzymes enabled us to establish the spatial organization of the ZFP gene cluster, the OATL1 pseudogene, the recurrent t(X;18) chromosome translocation breakpoint in synovial sarcoma, and the previously described cluster of ARAF1, SYN1, TIMP, and PFC genes. We have assigned the ETS-related gene ELK1 to a locus tightly linked to the PFC gene; the entire cluster of five genes is contained within a distance of 120 kb. ZNF41 maps to a 440-kb YAC spanning this region, while a more proximal cluster comprising the ZNF21 and ZNF81 genes lies 150 kb distal to the chromosome breakpoint associated with synovial sarcoma.

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Cited by (22)

ZNF674: A new Krüppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation
2006, American Journal of Human Genetics
Citation Excerpt :
In Xp11, three zinc-finger genes have been described to be involved in XLMR—ZNF41, ZNF81, and ZNF674. These genes are part of a KRAB-ZFP gene cluster in this region, which includes ZNF673, ZNF674, ZNF157 (MIM 300024) (Derry et al. 1995), ZNF41 (Shoichet et al. 2003), ZNF81 (Kleefstra et al. 2004), ZNF21 (MIM 314993) (Knight et al. 1994), and ZNF630. A position-specific iterated BLAST with the full-length ZNF674 protein sequence versus all human proteins revealed a subtree of 32 proteins derived from a tree of 500 proteins total.
Array-based comparative genomic hybridization has proven to be successful in the identification of genetic defects in disorders involving mental retardation. Here, we studied a patient with learning disabilities, retinal dystrophy, and short stature. The family history was suggestive of an X-linked contiguous gene syndrome. Hybridization of full-coverage X-chromosomal bacterial artificial chromosome arrays revealed a deletion of ∼1 Mb in Xp11.3, which harbors RP2, SLC9A7, CHST7, and two hypothetical zinc-finger genes, ZNF673 and ZNF674. These genes were analyzed in 28 families with nonsyndromic X-linked mental retardation (XLMR) that show linkage to Xp11.3; the analysis revealed a nonsense mutation, p.E118X, in the coding sequence of ZNF674 in one family. This mutation is predicted to result in a truncated protein containing the Krüppel-associated box domains but lacking the zinc-finger domains, which are crucial for DNA binding. We characterized the complete ZNF674 gene structure and subsequently tested an additional 306 patients with XLMR for mutations by direct sequencing. Two amino acid substitutions, p.T343M and p.P412L, were identified that were not found in unaffected individuals. The proline at position 412 is conserved between species and is predicted by molecular modeling to reduce the DNA-binding properties of ZNF674. The p.T343M transition is probably a polymorphism, because the homologous ZNF674 gene in chimpanzee has a methionine at that position. ZNF674 belongs to a cluster of seven highly related zinc-finger genes in Xp11, two of which (ZNF41 and ZNF81) were implicated previously in XLMR. Identification of ZNF674 as the third XLMR gene in this cluster may indicate a common role for these zinc-finger genes that is crucial to human cognitive functioning.
Physical map covering a 2 Mb region in human Xp11.3 distal to DX6849
1999, Gene
A 2 Mb contig was constructed of yeast artificial chromosomes (YACs) and P1 artificial chromosomes (PACs), extending from DXS6849 to a new marker EC7034R, 1 Mb distal to UBE1, within the p11.3 region of the human X chromosome. This contig, which has on average four-fold cloned coverage, was assembled using 37 markers, including 13 new sequence tagged sites (STSs) developed from YAC and PAC end-fragments, for an average inter-marker distance of 55 kb. The inferred marker order predicted from SEGMAP analysis, STS content and cell hybrid data is Xpter–EC7034R–EC8058R–FB20E11–DXS7804–DXS8308–(DXS1264, DXS1055)–DXS1003–UBE1–(UHX), PCTK1)–DXS1364–DXS1266–DXS337–SYN1–DXS6849-cen. One (TC)_n dinucleotide sequence from an end-clone was identified and found to be polymorphic (48% heterozygosity). The contig is merged with published physical maps both in the distal and in the centromeric direction of Xp, and provides reagents to aid in the DNA sequencing and the finding of genes in this region of the human genome.
Polymorphic X-chromosome inactivation of the human TIMP1 gene
1999, American Journal of Human Genetics
X inactivation silences most but not all of the genes on one of the two X chromosomes in mammalian females. The human X chromosome preserves its activation status when isolated in rodent/human somatic-cell hybrids, and hybrids retaining either the active or inactive X chromosome have been used to assess the inactivation status of many X-linked genes. Surprisingly, the X-linked gene for human tissue inhibitor of metalloproteinases (TIMP1) is expressed in some but not all inactive X-containing somatic-cell hybrids, suggesting that this gene is either prone to reactivation or variable in its inactivation. Since many genes that escape X inactivation are clustered, we examined the expression of four genes (ARAF1, ELK1, ZNF41, and ZNF157) within ∼100 kb of TIMP1. All four genes were expressed only from the active X chromosome, demonstrating that the factors allowing TIMP1 expression from the inactive X chromosome are specific to the TIMP1 gene. To determine if this variable inactivation of TIMP1 is a function of the hybrid-cell environment or also is observed in human cells, we developed an allele-specific assay to assess TIMP1 expression in human females. Expression of two alleles was detected in some female cells with previously demonstrated extreme skewing of X inactivation, indicating TIMP1 expression from the inactive chromosome. However, in other cells, no expression of TIMP1 was observed from the inactive X chromosome, suggesting that TIMP1 inactivation is polymorphic in human females.
Construction of a 1.5-Mb bacterial artificial chromosome contig in Xp11.23, a Region of high gene content
1998, Genomics
To generate sequence-ready templates for the gene-rich Xp11.23 region, we have constructed a 1.5-Mb bacterial artificial chromosome (BAC) contig spanning the interval between the DNA markers OATL1 and DXS255. The contig includes 28 BACs, ranging in size from 58 to 285 kb with an average size of 135 kb, which provide 2.5-fold coverage of the region. The BAC contig was constructed based entirely on the content of 40 DNA markers from a previously established YAC contig and 11 new markers developed from BAC-end DNA sequences, 4 of which were required to close gaps in the map. There was no evidence of rearrangement, instability, or chimerism in any of the BAC clones. The BAC cloning system appears to provide robust and total physical coverage of this gene-rich region with clones that are suitable for DNA sequencing.
Cloning, chromosomal localization, physical mapping, and genomic characterization of HKR3
1996, Genomics
TheKrüppel-type zinc finger proteins are members of a conserved family of transcription factors that are important in developmental regulation. Altered expression of several of these proteins has been implicated in human diseases, including cancer. We report the cloning, mapping, and characterization of the zinc finger geneHuman Krüppel-Related 3(HKR3). Genomic clones ofHKR3were isolated from a P1 library and localized to human chromosome subband 1p36.3 by human–rodent somatic cell hybrid mapping and fluorescencein situhybridization. The gene was physically mapped to within 40 kb ofD1S214by YAC content and long-range restriction mapping.HKR3spans 9.5 kb of genomic DNA and is contained in 11 exons. Sequencing defined each of the exon/intron splice site junctions and identified a CpG island in the 5′ region of the gene.HKR3is ubiquitously expressed in human tissues as at least two major transcripts, the shorter of which excludes a conserved finger-associated box and a putative acidic activation domain contained in the full-length transcript.HKR3is a novel zinc finger gene that maps to a region of the genome commonly rearranged or deleted in human cancers.
A 2-megabase physical contig incorporating 43 DNA markers on the human X chromosome at p11.23-p11.22 from ZNF21 to DXS255
1996, Genomics
A comprehensive physical contig of yeast artificial chromosomes (YACs) and cosmid clones between ZNF21 and DXS255 has been constructed, spanning 2 Mb within the region Xp11.23–p11.22. As a portion of the region was found to be particularly unstable in yeast, the integrity of the contig is dependent on additional information provided by the sequence-tagged site (STS) content of cosmid clones and DNA marker retention in conventional and radiation hybrids. The contig was formatted with 43 DNA markers, including 19 new STSs from YAC insert ends and an internalAlu-PCR product. The density of STSs across the contig ranges from one marker every 20 kb to one every 60 kb, with an average density of one marker every 50 kb. The relative order of previously known genes and expressed sequence tags in this region is predicted to be Xpter–ZNF21–DXS7465E (MG66)–DXS7927E (MG81)–WASP, DXS1011E, DXS7467E (MG21)–DXS- 7466E (MG44)–GATA1–DXS7469E (Xp664)–TFE3–SYP (DXS1007E)–Xcen. This contig extends the coverage in Xp11 and provides a framework for the future identification and mapping of new genes, as well as the resources for developing DNA sequencing templates.

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Regular ArticleClustered Organization of Krüppel Zinc-Finger Genes at Xp11.23, Flanking a Translocation Breakpoint at OATL1: A Physical Map with Locus Assignments for ZNF21, ZNF41, ZNF81, and ELK1

Abstract

Regular Article
Clustered Organization of Krüppel Zinc-Finger Genes at Xp11.23, Flanking a Translocation Breakpoint at OATL1: A Physical Map with Locus Assignments for ZNF21, ZNF41, ZNF81, and ELK1