Mutations in the ZNF41 Gene Are Associated with Cognitive Deficits: Identification of a New Candidate for X-Linked Mental Retardation

Abstract

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.

Identification of ANKRD11 and ZNF778 as candidate genes for autism and variable cognitive impairment in the novel 16q24.3 microdeletion syndrome

“…KRAB-domain zinc finger proteins are found in transcription regulatory complexes, which are directed to the regulatory elements of target genes through the C2H2 zinc finger domains that recognize specific DNA binding sites. Moreover, several human zinc finger genes have been associated with MR: ZNF41 (MIM 314995), ZNF81 (MIM 314998) and ZNF674 (MIM 300573) with X-linked MR [39][40][41] and ZNF385B (MIM 612344) with the 2q31.2 deletion syndrome. 41 Therefore, haploinsufficiency of ZNF778 might also, or exclusively, be involved in the phenotype observed in the reported patients.…”

Zinc finger 81 (ZNF81) mutations associated with X-linked mental retardation

“…However in MRX, only 15 genes are known to be involved accounting for less than one-fifth of all MRX. [1][2][3][4][5][6] The recent observations that RSK2, MECP2, and ARX play a role in both syndromic and non-syndromic forms of XLMR, [7][8][9][10] suggest that a molecular basis to strictly separate these two forms is not always present. In addition, careful clinical re-examination of patients with an OPHN1 gene mutation has revealed distinctive phenotypic hallmarks, such as cerebellar hypoplasia, in patients who were previously classified as nonsyndromic.…”

“…Recently, it has been predicted that approximately 30% of all mutations underlying MRX are located in the Xp11.2-Xp11.3 interval. 1 Only two MRX genes have so far been identified in this region, ZNF41 5 and PQBP1. 6 In this study, we have characterised the breakpoint of a de novo translocation t(X;9)(p11.23;q34.3) in a female patient with severe mental retardation.…”

Loss of ZDHHC15 expression in a woman with a balanced translocation t(X;15)(q13.3;cen) and severe mental retardation

“…A mutation in ARHGEF6 [MIM 300267], which is reported in nonsyndromic XLMR, was identified in one of 119 affected families screened. 19 Shoichet et al 8 reported alterations in ZNF41 [MIM 314995] in two out of 210 unrelated mentally retarded patients analysed. Therefore, more patients need to be investigated in search for XLMR-associated mutations in ZDHHC15.…”

“…Genes on the X chromosome disrupted by balanced X;autosome translocations in female subjects with MR are good candidate genes as they usually have only one functional copy. 7,8 The normal allele is inactive in most female carriers of such balanced translocations due to skewed X-inactivation with the derivative X chromosome retained active. 9 In this study, we investigated the translocation breakpoints in a female patient with severe, nonsyndromic MR who carries a de novo balanced translocation t(X;15).…”