HGNC Approved Gene Symbol: ZNF41
Cytogenetic location: Xp11.3 Genomic coordinates (GRCh38): X:47,445,178-47,483,222 (from NCBI)
Zinc finger domains, loop-like motifs formed by the interaction of 2 invariant pairs of cysteines and histidines with a zinc ion, were first described in transcription factor IIIA in Xenopus oocytes (Miller et al., 1985). Franze et al. (1991) isolated a novel human zinc finger gene, ZNF41, from a human X-chromosome-specific library. Nucleotide sequence analysis showed that ZNF41 potentially encodes a polypeptide featuring an array of 18 contiguous zinc fingers of the C2H2 type. Multiple polyadenylated transcripts homologous to ZNF41 are present at different levels in several distinct cell types.
Rosati et al. (1999) reported that ZNF41 contains a KRAB/FPB (Kruppel-associated/finger preceding box) domain, a potent transcription repression motif composed of 2 protein modules, A and B.
By Southern analysis of somatic cell hybrids containing either intact or rearranged X chromosomes, Franze et al. (1991) confirmed the genomic origin of the ZNF41 gene and regionalized the assignment to Xp22.1-cen where several other zinc finger genes. Rosati et al. (1999) stated that the ZNF41 gene maps to Xp11.3 and found that the gene escapes X inactivation.
Rosati et al. (1999) determined that the ZNF41 gene contains 4 exons.
Shoichet et al. (2003) described a female patient with severe nonsyndromic mental retardation (MRX89; 300848) and a de novo balanced translocation t(X;7)(p11.3;q11.21) in whom they cloned the DNA fragment that contained the X chromosomal and the autosomal breakpoint. In silico sequence analysis demonstrated that the ZNF41 gene was disrupted. Expression studies indicated that ZNF41 transcripts were absent in the patient cell line, suggesting that the mental disorder in this patient resulted from loss of functional ZNF41. Moreover, screening of a panel of patients with MRX led to the identification of 2 other ZNF41 mutations (314995.0001-314995.0002) that were not found in healthy control individuals.
Based on their finding of the mutations in ZNF41 identified by Shoichet et al. (2003) in a total of 7 males in the NHLBI Exome Variant Server, and the additional finding of truncating ZNF41 variants in 1 male and 1 female in that database, Piton et al. (2013) classified the involvement of ZNF41 in mental retardation as highly questionable.
This variant, formerly titled MENTAL RETARDATION, X-LINKED 89 based on the report of Shoichet et al. (2003), has been reclassified based on the findings of Piton et al. (2013).
In a male patient with X-linked mental retardation (300848), Shoichet et al. (2003) identified a 738C-T transition in the ZNF41 gene, predicted to result in a pro111-to-leu (P111L) amino acid change. The mutation was also found in his affected brother. The index patient had delayed early milestones and at the age of 5 years was functioning at an intellectual level of age 3 years. He exhibited language retardation, avoided social contact, and was hyperactive. He had no dysmorphic features or additional neurologic abnormalities. Both of the mother's brothers were affected but further clinical data were not available. The mother was shown to carry the mutation, which was not found in 401 control chromosomes.
Piton et al. (2013) identified the P111L variant of ZNF41 in 2 males and 8 females in the NHLBI Exome Variant Server.
This variant, formerly titled MENTAL RETARDATION, X-LINKED 89 based on the report of Shoichet et al. (2003), has been reclassified based on the findings of Piton et al. (2013).
In a male patient with X-linked mental retardation (300848), Shoichet et al. (2003) identified an intronic adenine-to-cytidine splice site mutation, 479-42A-C, that resulted in loss of specific ZNF41 splice variants. The patient reached early milestones within the normal time frame, but exhibited a severe language delay. At age 10 years, he was unable to read, had essentially no acquisition of mathematics skills, had mood disorders, with both hyperactivity and aggressiveness, and required special education. He had no dysmorphic features or additional neurologic abnormalities. The mutation was found in heterozygosity in the patient's mildly affected sister. The mother was shown to carry the mutation, which was not found in 405 control chromosomes.
Piton et al. (2013) identified the c.73-42A-C variant of ZNF41 in 5 males and 9 females in the NHLBI Exome Variant Server.
Franze, A., Archidiacono, N., Rocchi, M., Marino, M., Grimaldi, G. Isolation and expression analysis of a human zinc finger gene (ZNF41) located on the short arm of the X chromosome. Genomics 9: 728-736, 1991. [PubMed: 2037297] [Full Text: https://doi.org/10.1016/0888-7543(91)90367-n]
Miller, J., McLachlan, A. D., Klug, A. Repetitive zinc-binding domains in the protein transcription factor IIIA from Xenopus oocytes. EMBO J. 4: 1609-1614, 1985. [PubMed: 4040853] [Full Text: https://doi.org/10.1002/j.1460-2075.1985.tb03825.x]
Piton, A., Redin, C., Mandel, J.-L. XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing. Am. J. Hum. Genet. 93: 368-383, 2013. Note: Erratum: Am. J. Hum. Genet. 93: 406 only, 2013. [PubMed: 23871722] [Full Text: https://doi.org/10.1016/j.ajhg.2013.06.013]
Rosati, M., Franze, A., Matarazzo, M. R., Grimaldi, G. Coding region intron/exon organization, alternative splicing, and X-chromosome inactivation of the KRAB/FPB-domain-containing human zinc finger gene ZNF41. Cytogenet. Cell Genet. 85: 291-296, 1999. [PubMed: 10449920] [Full Text: https://doi.org/10.1159/000015315]
Shoichet, S. A., Hoffmann, K., Menzel, C., Trautmann, U., Moser, B., Hoeltzenbein, M., Echenne, B., Partington, M., van Bokhoven, H., Moraine, C., Fryns, J.-P., Chelly, J., Rott, H.-D., Ropers, H.-H., Kalscheuer, V. M. Mutations in the ZNF41 gene are associated with cognitive deficits: identification of a new candidate for X-linked mental retardation. Am. J. Hum. Genet. 73: 1341-1354, 2003. [PubMed: 14628291] [Full Text: https://doi.org/10.1086/380309]