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.
Lugtenberg
Dorien
D
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Yntema
Helger G
HG
Banning
Martijn J G
MJ
Oudakker
Astrid R
AR
Firth
Helen V
HV
Willatt
Lionel
L
Raynaud
Martine
M
Kleefstra
Tjitske
T
Fryns
Jean-Pierre
JP
Ropers
Hans-Hilger
HH
Chelly
Jamel
J
Moraine
Claude
C
Gecz
Jozef
J
van Reeuwijk
Jeroen
J
Nabuurs
Sander B
SB
de Vries
Bert B A
BB
Hamel
Ben C J
BC
de Brouwer
Arjan P M
AP
van Bokhoven
Hans
H
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000737:chemistry / Q000145:classification / Q000235:genetics*; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010802:Phylogeny; D011487:Protein Conformation; D016335:Zinc Fingers
D051741:Kruppel-Like Transcription Factors; C523963:ZNF674 protein, human