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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents

ID: 307723.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
ZNF674: a new KRAB-containing zinc finger gene involved in non-syndromic X-linked mental retardation
Authors:Lugtenberg, Dorien; Yntema, Helger G.; Banning, Martijn J. G.; Oudakker, Astrid R.; Firth, Helen V.; Willatt, Lionel; Raynaud, Martine; Kleefstra, Tjitske; Fryns, Jean-Pierre; Ropers, Hans-Hilger; Chelly, Jamel; Moraine, Claude; Gécz, Jozef; van Reeuwijk, Jeroen; Nabuurs, Sander B.; de Vries, Bert B. A.; Hamel, Ben C. J.; de Brouwer, Arjan P. M.; van Bokhoven, Hans
Date of Publication (YYYY-MM-DD):2006-02-01
Title of Journal:American Journal of Human Genetics : : AJHG / American Society of Human Genetics
Journal Abbrev.:Am. J. Hum. Genet.
Issue / Number:2
Start Page:265
End Page:278
Copyright:© 2006 by The American Society of Human Genetics. All rights reserved.
Review Status:not specified
Audience:Experts Only
Abstract / Description: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.
External Publication Status:published
Document Type:Article
Version Comment:Automatic journal name synchronization
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Department of Human Genetics, Radboud University Nijmegen Medical Centre, and Centre for Molecular and Biomolecular Informatics, Radboud University Nijmegen, Nijmegen, The Netherlands;
2.Department of Clinical Genetics, Addenbrooke's Hospital, Cambridge, United Kingdom;
3.Service de Génétique et INSERM U316, Hôpital Bretonneau, Tours, France;
4.Center for Human Genetics, University of Leuven, Leuven, Belgium;
5.NSERM 129-ICGM, Faculté de Médecine Cochin, Paris, France;
6.Department of Genetic Medicine, Women's and Children's Hospital and Department of Paediatrics, University of Adelaide, Adelaide, Australia.
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