Mutations in the ZNF41 gene are associated with cognitive deficits: identification of a new candidate for X-linked mental retardation

Am J Hum Genet. 2003 Dec;73(6):1341-54. doi: 10.1086/380309. Epub 2003 Nov 18.


Nonsyndromic X-linked mental retardation (MRX) is defined by an X-linked inheritance pattern of low IQ, problems with adaptive behavior, and the absence of additional specific clinical features. The 13 MRX genes identified to date account for less than one-fifth of all MRX, suggesting that numerous gene defects cause the disorder in other families. In a female patient with severe nonsyndromic mental retardation and a de novo balanced translocation t(X;7)(p11.3;q11.21), we have cloned the DNA fragment that contains the X-chromosomal and the autosomal breakpoint. In silico sequence analysis provided no indication of a causative role for the chromosome 7 breakpoint in mental retardation (MR), whereas, on the X chromosome, a zinc-finger gene, ZNF41, was found to be disrupted. Expression studies indicated that ZNF41 transcripts are absent in the patient cell line, suggesting that the mental disorder in this patient results from loss of functional ZNF41. Moreover, screening of a panel of patients with MRX led to the identification of two other ZNF41 mutations that were not found in healthy control individuals. A proline-to-leucine amino acid exchange is present in affected members of one family with MRX. A second family carries an intronic splice-site mutation that results in loss of specific ZNF41 splice variants. Wild-type ZNF41 contains a highly conserved transcriptional repressor domain that is linked to mechanisms of chromatin remodeling, a process that is defective in various other forms of MR. Our results suggest that ZNF41 is critical for cognitive development; further studies aim to elucidate the specific mechanisms by which ZNF41 alterations lead to MR.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Base Sequence
  • Blotting, Northern
  • Blotting, Southern
  • Chromatin Assembly and Disassembly / genetics
  • Chromatography, High Pressure Liquid
  • Chromosome Mapping
  • Chromosomes, Human, X / genetics*
  • Cognition Disorders / genetics*
  • DNA Primers
  • DNA-Binding Proteins / genetics*
  • Female
  • Gene Expression / genetics
  • Humans
  • In Situ Hybridization, Fluorescence
  • Kruppel-Like Transcription Factors
  • Mental Retardation, X-Linked / genetics*
  • Molecular Sequence Data
  • Mutation / genetics*
  • Pedigree
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Analysis, DNA


  • DNA Primers
  • DNA-Binding Proteins
  • Kruppel-Like Transcription Factors
  • ZNF41 protein, human

Associated data

  • GENBANK/AC069285
  • GENBANK/AJ010018
  • GENBANK/AJ010021
  • GENBANK/AL009172
  • GENBANK/AL022165
  • GENBANK/AL022578
  • GENBANK/AL023623
  • GENBANK/AL031967
  • GENBANK/AL139811
  • GENBANK/AL162583
  • GENBANK/AL359698
  • GENBANK/AL590223
  • GENBANK/AL590283
  • GENBANK/AL591503
  • GENBANK/AQ003212
  • GENBANK/BC041841
  • GENBANK/Z83822