ZNF674: A new Krüppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation

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, Hans Van Bokhoven

Research output: Contribution to journalArticle

62 Citations (Scopus)

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.

LanguageEnglish
Pages265-278
Number of pages14
JournalAmerican Journal of Human Genetics
Volume78
Issue number2
DOIs
Publication statusPublished - 1 Jan 2006
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Lugtenberg, D., Yntema, H. G., Banning, M. J. G., Oudakker, A. R., Firth, H. V., Willatt, L., ... Van Bokhoven, H. (2006). ZNF674: A new Krüppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation. American Journal of Human Genetics, 78(2), 265-278. https://doi.org/10.1086/500306
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. / ZNF674 : A new Krüppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation. In: American Journal of Human Genetics. 2006 ; Vol. 78, No. 2. pp. 265-278.
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Lugtenberg, D, Yntema, HG, Banning, MJG, Oudakker, AR, Firth, HV, Willatt, L, Raynaud, M, Kleefstra, T, Fryns, JP, Ropers, HH, Chelly, J, Moraine, C, Gécz, J, Van Reeuwijk, J, Nabuurs, SB, De Vries, BBA, Hamel, BCJ, De Brouwer, APM & Van Bokhoven, H 2006, 'ZNF674: A new Krüppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation', American Journal of Human Genetics, vol. 78, no. 2, pp. 265-278. https://doi.org/10.1086/500306

ZNF674 : A new Krüppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation. / 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.

In: American Journal of Human Genetics, Vol. 78, No. 2, 01.01.2006, p. 265-278.

Research output: Contribution to journalArticle

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AU - Firth, Helen V.

AU - Willatt, Lionel

AU - Raynaud, Martine

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AU - Ropers, Hans Hilger

AU - Chelly, Jamel

AU - Moraine, Claude

AU - Gécz, Jozef

AU - Van Reeuwijk, Jeroen

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AU - Van Bokhoven, Hans

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