TY - JOUR
T1 - ZNF674
T2 - A new Krüppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation
AU - Lugtenberg, Dorien
AU - Yntema, Helger G.
AU - Banning, Martijn J.G.
AU - Oudakker, Astrid R.
AU - Firth, Helen V.
AU - Willatt, Lionel
AU - Raynaud, Martine
AU - Kleefstra, Tjitske
AU - Fryns, Jean Pierre
AU - Ropers, Hans Hilger
AU - Chelly, Jamel
AU - Moraine, Claude
AU - Gécz, Jozef
AU - Van Reeuwijk, Jeroen
AU - Nabuurs, Sander B.
AU - De Vries, Bert B.A.
AU - Hamel, Ben C.J.
AU - De Brouwer, Arjan P.M.
AU - Van Bokhoven, Hans
N1 - Funding Information:
We thank the families for their cooperation in this research. We are indebted to C. Beumer for culturing the patient cell lines. We also thank J. Bokhorst for expert technical assistance. This work was supported by grant QLG3-CT-2002-01810 (EURO-MRX) from the European Union and grant H02.10 (HGY) from the Hersenstichting Nederland.
PY - 2006/2
Y1 - 2006/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=31544453949&partnerID=8YFLogxK
U2 - 10.1086/500306
DO - 10.1086/500306
M3 - Article
C2 - 16385466
AN - SCOPUS:31544453949
VL - 78
SP - 265
EP - 278
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 2
ER -