Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/23254
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Type: Journal article
Title: ZNF674: A new Kruppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation
Author: Lugtenberg, D.
Yntema, H.
Banning, M.
Oudakker, A.
Firth, H.
Willatt, L.
Raynaud, M.
Kleefstra, T.
Fryns, J.
Ropers, H.
Chelly, J.
Moraine, C.
Gecz, J.
van Reeuwijk, J.
Nabuurs, S.
de Vries, B.
Hamel, B.
de Brouwer, A.
van Bokhoven, H.
Citation: American Journal of Human Genetics, 2006; 78(2):265-278
Publisher: Univ Chicago Press
Issue Date: 2006
ISSN: 0002-9297
1537-6605
Statement of
Responsibility: 
Dorien Lugtenberg, Helger G. Yntema, Martijn J. G. Banning, Astrid R. Oudakker, Helen V. Firth, Lionel Willatt, Martine Raynaud, Tjitske Kleefstra, Jean-Pierre Fryns, Hans-Hilger Ropers, Jamel Chelly, Claude Moraine, Jozef Gécz, Jeroen van Reeuwijk, Sander B. Nabuurs, Bert B. A. de Vries, Ben C. J. Hamel, Arjan P. M. de Brouwer and Hans van Bokhoven.
Abstract: 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.
Keywords: Humans; Mental Retardation, X-Linked; Amino Acid Substitution; Phylogeny; Amino Acid Sequence; Protein Conformation; Zinc Fingers; Mutation; Models, Molecular; Molecular Sequence Data; Child; Child, Preschool; Female; Male; Kruppel-Like Transcription Factors
Rights: Copyright © 2006 The American Society of Human Genetics Published by Elsevier Inc.
RMID: 0020060521
DOI: 10.1086/500306
Appears in Collections:Paediatrics publications

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