Clinical findings and a DNA methylation signature in kindreds with alterations in ZNF711

Wang, Jiyong; Richardson, Ellen; Skinner, Steven A.; Reilly, Jack; Kerkhof, Jennifer; Curry, Cynthia J.; Tarpey, Patrick; Robertson, Stephen P.; Maystadt, Isabelle; Keren, Boris; Dixon, Joanne; Skinner, Cindy; Stapleton, Rachel; Ruaud, Lyse; Gumus, Evren; Lakeman, Phillis; Alders, Mariëlle; Tedder, Matthew L.; Schwartz, Charles E.; Friez, Michael J.; Sadiković, Bekim; Stevenson, Roger E.

doi:10.1038/s41431-021-01018-1

Cited by 12 publications

(14 citation statements)

References 33 publications

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“…DNA methylation signatures in autism have been reported [ 22 ] and recent studies show a DNA methylation signature in autism associated with Mecp2 [ 23 ] and CHD8 [ 24 ]. Wang and colleagues [ 25 ] report on DNA methylation signature with nonsyndromic nature of intellectual disability associated with ZNF711 .…”

Section: Resultsmentioning

confidence: 99%

Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case Report

Clothier

Grooms

Porter-Gill

et al. 2022

JPM

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Autism spectrum disorder (ASD) comprises a heterogeneous group of neurodevelopmental disorders and occurs in all racial, ethnic, and socioeconomic groups. Cutting-edge technologies are contributing to understanding genetic underpinnings in ASD. The reported patient is a 32-year-old male and as an infant was noted to have microcephaly, hypospadias, pulmonary vascular anomaly, and small stature. He was diagnosed with Cornelia De Lange Syndrome (CDLS) at that time based on the clinical features. As a child, he had autistic features and intellectual disabilities and as diagnoses with autism and intellectual disability. He was referred as an adult to our neurodiversity clinic and a full exome trio sequencing with reflex to mitochondrial genes identified a de novo variant of uncertain significance in a candidate gene, DCAF1. The specific variant was c.137 C > T (p.Thr46Ile) in exon 4 in the DCAF1 gene. In silico analysis supports a deleterious effect on protein structure/function. DCAF1 participates with DDB1 and CUL4 as a part of the E3 ubiquitin ligase complex. The E3 ligase complex has been associated with a syndromic form of X-linked intellectual disability. The DDB1/CUL4 E3 ubiquitination complex plays a role in methylation-dependent ubiquitination. Next, a methylation study identified a signature similar to the methylation pattern found in X- linked intellectual disability type 93. This is associated with variants of the BRWD3 gene, which is linked with the functioning of the DDB1/CUL4 E3 ubiquitination complex. Taken together, this suggests that the de novo DCAF1 variant may be a newly identified molecular cause of autism and intellectual disability.

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Section: Resultsmentioning

confidence: 99%

Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case Report

Clothier

Grooms

Porter-Gill

et al. 2022

JPM

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“…Sequence alterations in ZNF711 have been identified in a number of families with nonsyndromic XLID, including IDX40, IDX65, and IDX97 37 . The intellectual disability is typically mild and coexists with autism spectrum disorder in half of cases.…”

Section: Duplications Of Xlid Genesmentioning

confidence: 99%

Clinical findings in individuals with duplication of genes associated with X‐linked intellectual disability

Sahajpal,

Ziats,

Chaubey

et al. 2023

Clinical Genetics

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Duplication of all genes associated with X‐linked intellectual disability (XLID) have been reported but the majority of the duplications include more than one XLID gene. It is exceptional for whole XLID gene duplications to cause the same phenotype as sequence variants or deletions of the same gene. Duplication of PLP1, the gene associated with Pelizaeus‐Merzbacher syndrome, is the most notable duplication of this type. More commonly, duplication of XLID genes results in very different phenotypes than sequence alterations or deletions. Duplication of MECP2 is widely recognized as a duplication of this type, but a number of others exist. The phenotypes associated with gene duplications are often milder than those caused by deletions and sequence variants. Among some duplications that are clinically significant, marked skewing of X‐inactivation in female carriers has been observed. This report describes the phenotypic consequences of duplication of 22 individual XLID genes, of which 10 are described for the first time.

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“…2017; Wang J et al 2022). There are some 82 genes on the X-chromosome associated with intellectual disability (Kleine-Kohlbrecher et al 2010).…”

Section: Introductionmentioning

confidence: 99%

“…There are some 82 genes on the X-chromosome associated with intellectual disability (Kleine-Kohlbrecher et al 2010). ZNF711 is one of eleven of these proteins containing ZNF domains (Wang J et al 2022). The NIH deemed ZNF711 an understudied protein associated with a rare disease, part of an effort to jumpstart research efforts in this area under the program RFA-TR-22-030.…”

Section: Introductionmentioning

confidence: 99%

Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure

Rua,

Alexandrescu

2024

Preprint

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Domain Z7 of nuclear transcription factor ZNF711 has the consensus last metal-ligand H23 found in odd-numbered zinc-fingers of this protein replaced by a phenylalanine. Ever since the discovery of ZNF711 it has been thought that Z7 is probably non-functional because of the H23F substitution. The presence of H26 three positions downstream prompted us to examine if this histidine could substitute as the last metal ligand. The Z7 domain adopts a stable tertiary structure upon metal binding. The NMR structure of Zn2+-bound Z7 shows the classical ββα-fold of CCHH zinc fingers. Mutagenesis and pH titration experiments indicate that H26 is not involved in metal binding and that Z7 has a tridentate metal-binding site comprised of only residues C3, C6, and H19. By contrast, an F23H mutation that introduces a histidine in the consensus position forms a tetradentate ligand. The structure of the WT Z7 is stable causing restricted ring-flipping of phenyalanines 10 and 23. Dynamics are increased with either the H26A or F23H substitutions and aromatic ring rotation is no longer hindered in the two mutants. The mutations have only small effects on the Kd values for Zn2+and Co2+and retain the high thermal stability of the WT domain above 80oC. Like two previously reported designed zinc fingers with the last ligand replaced by water, the WT Z7 domain is catalytically active, hydrolyzing 4-nitophenyl acetate. We discuss the implications of naturally occurring tridentate zinc fingers for cancer mutations and drug targeting of notoriously undruggable transcription factors. Our findings that Z7 can fold with only a subset of three metal ligands suggests the recent view that most everything about protein structure can be predicted through homology modeling might be premature for at least the resilient and versatile zinc-finger motif.

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Clinical findings and a DNA methylation signature in kindreds with alterations in ZNF711

Cited by 12 publications

References 33 publications

Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case Report

Identification of DCAF1 by Clinical Exome Sequencing and Methylation Analysis as a Candidate Gene for Autism and Intellectual Disability: A Case Report

Clinical findings in individuals with duplication of genes associated with X‐linked intellectual disability

Formerly degenerate seventh zinc finger domain from transcription factor ZNF711 rehabilitated by experimental NMR structure

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