ZNF674: a new kruppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation.

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 Kruppel-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.

[1]  Thomas L. Madden,et al.  Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. , 1997, Nucleic acids research.

[2]  D. Higgs,et al.  Mutations in a putative global transcriptional regulator cause X-linked mental retardation with α-thalassemia (ATR-X syndrome) , 1995, Cell.

[3]  H. Ropers,et al.  Zinc finger 81 (ZNF81) mutations associated with X-linked mental retardation , 2004, Journal of Medical Genetics.

[4]  H. Ropers,et al.  Mutations in the ZNF41 gene are associated with cognitive deficits: identification of a new candidate for X-linked mental retardation. , 2003, American journal of human genetics.

[5]  H. Ropers,et al.  X-linked mental retardation , 2005, Nature Reviews Genetics.

[6]  J. Berg,et al.  A 2.2 Å resolution crystal structure of a designed zinc finger protein bound to DNA , 1996, Nature Structural Biology.

[7]  Han G Brunner,et al.  High-throughput analysis of subtelomeric chromosome rearrangements by use of array-based comparative genomic hybridization. , 2002, American journal of human genetics.

[8]  D. Horn,et al.  Familial MCA/MR syndrome due to inherited submicroscopic translocation t(18;21)(q22.1q21.3) with breakpoint at the Down syndrome critical region , 2003, American journal of medical genetics. Part A.

[9]  Gert Vriend,et al.  Making optimal use of empirical energy functions: Force‐field parameterization in crystal space , 2004, Proteins.

[10]  Han G Brunner,et al.  Mutations in a new member of the chromodomain gene family cause CHARGE syndrome , 2004, Nature Genetics.

[11]  C. Fletcher,et al.  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. , 1994, Genomics.

[12]  J. Mandel,et al.  Monogenic X-linked mental retardation: Is it as frequent as currently estimated? The paradox of the ARX (Aristaless X) mutations , 2004, European Journal of Human Genetics.

[13]  G. Maul,et al.  SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. , 2002, Genes & development.

[14]  E. Ballestar,et al.  Methyl-CpG-binding proteins. Targeting specific gene repression. , 2001, European journal of biochemistry.

[15]  N. Saitou,et al.  The neighbor-joining method: a new method for reconstructing phylogenetic trees. , 1987, Molecular biology and evolution.

[16]  P. D. de Jong,et al.  High resolution profiling of X chromosomal aberrations by array comparative genomic hybridisation , 2004, Journal of Medical Genetics.

[17]  A Klug,et al.  A role in DNA binding for the linker sequences of the first three zinc fingers of TFIIIA. , 1993, Nucleic acids research.

[18]  H. Dyson,et al.  DNA-induced α-helix capping in conserved linker sequences is a determinant of binding affinity in Cys2-His2 zinc fingers , 2000 .

[19]  M. Carter,et al.  A splicing‐dependent regulatory mechanism that detects translation signals. , 1996, The EMBO journal.

[20]  N. Carter,et al.  Applications of genomic microarrays to explore human chromosome structure and function. , 2004, Human molecular genetics.

[21]  M. Ladomery,et al.  Multifunctional zinc finger proteins in development and disease , 2002 .

[22]  J. Friedman,et al.  Targeting histone deacetylase complexes via KRAB-zinc finger proteins: the PHD and bromodomains of KAP-1 form a cooperative unit that recruits a novel isoform of the Mi-2alpha subunit of NuRD. , 2001, Genes & development.

[23]  Robert L. Schalock,et al.  Mental Retardation: Definition, Classification, and Systems of Supports. 10th Edition. , 2002 .

[24]  Adrian A Canutescu,et al.  Access the most recent version at doi: 10.1110/ps.03154503 References , 2003 .

[25]  J. Martial,et al.  The evolutionarily conserved Krüppel-associated box domain defines a subfamily of eukaryotic multifingered proteins. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[26]  J. Gécz,et al.  Mutations in the JARID1C gene, which is involved in transcriptional regulation and chromatin remodeling, cause X-linked mental retardation. , 2005, American journal of human genetics.

[27]  J. Torchia,et al.  A Novel Nuclear Receptor Corepressor Complex, N-CoR, Contains Components of the Mammalian SWI/SNF Complex and the Corepressor KAP-1* , 2000, The Journal of Biological Chemistry.

[28]  Robert C. Edgar,et al.  MUSCLE: a multiple sequence alignment method with reduced time and space complexity , 2004, BMC Bioinformatics.

[29]  D. Speicher,et al.  KAP-1, a novel corepressor for the highly conserved KRAB repression domain. , 1996, Genes & development.

[30]  Prim B. Singh,et al.  KAP-1 Corepressor Protein Interacts and Colocalizes with Heterochromatic and Euchromatic HP1 Proteins: a Potential Role for Krüppel-Associated Box–Zinc Finger Proteins in Heterochromatin-Mediated Gene Silencing , 1999, Molecular and Cellular Biology.

[31]  O. Gascuel,et al.  A simple, fast, and accurate algorithm to estimate large phylogenies by maximum likelihood. , 2003, Systematic biology.

[32]  C. Sander,et al.  Errors in protein structures , 1996, Nature.

[33]  D. Case,et al.  Domain packing and dynamics in the DNA complex of the N-terminal zinc fingers of TFIIIA , 1997, Nature Structural Biology.

[34]  B. D. de Vries,et al.  Chromosomal copy number changes in patients with non-syndromic X linked mental retardation detected by array CGH , 2005, Journal of Medical Genetics.

[35]  U. Francke,et al.  Cloning and characterization of a novel zinc finger gene in Xp11.2. , 1995, Genomics.

[36]  Steffen Lenzner,et al.  Positional cloning of the gene for X-linked retinitis pigmentosa 2 , 1998, Nature Genetics.

[37]  A. Toutain,et al.  Systematic analysis of X-inactivation in 19 XLMR families: extremely skewed profiles in carriers in three families , 2000, European Journal of Human Genetics.

[38]  P E Wright,et al.  Solution structure of the first three zinc fingers of TFIIIA bound to the cognate DNA sequence: determinants of affinity and sequence specificity. , 1997, Journal of molecular biology.

[39]  S. Thukral,et al.  Alanine scanning site-directed mutagenesis of the zinc fingers of transcription factor ADR1: residues that contact DNA and that transactivate. , 1991, Proceedings of the National Academy of Sciences of the United States of America.