YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction

Gabriele, Michele; Silfhout, Anneke T. Vulto-van; Germain, Pierre-Luc; Vitriolo, Alessandro; Kumar, Raman; Douglas, Evelyn; Haan, Eric; Kosaki, Kenjiro; Tamura, Toshiki; Rauch, Anita; Steindl, Katharina; Frengen, Eirik; Misceo, Doriana; Pedurupillay, Christeen Ramane J.; Strømme, Petter; Rosenfeld, Jill A.; Shao, Yunru; Craigen, William J.; Schaaf, Christian P.; Rodriguez-Buritica, David; Farach, Laura S.; Friedman, Jennifer; Thulin, Perla; McLean, Scott; Nugent, Kimberly; Morton, Jenny; Nicholl, Jillian; Andrieux, Joris; Stray-Pedersen, Asbjørg; Chambon, Pascal; Patrier, Sophie; Lynch, Sally Ann; Kjærgaard, Susanne; Tørring, Pernille Mathiesen; Brasch‐Andersen, Charlotte; Ronan, Anne; Haeringen, Arie van; Anderson, Peter J.; Powis, Zöe; Brunner, Han G.; Pfundt, Rolph; Schuurs-Hoeijmakers, Janneke; Bon, Bregje W.M. van; Lelieveld, Stefan H.; Gilissen, Christian; Nillesen, Willy M.; Vissers, Lisenka E.L.M.; Gécz, Jozef; Koolen, David A.; Testa, Giuseppe; Vries, Bert B.A. de

doi:10.1016/j.ajhg.2017.05.006

Cited by 126 publications

(153 citation statements)

References 81 publications

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“…A cohort of patients with various mutations in one allele and exhibiting intellectual disability have been described as having a “YY1 syndrome,” and lymphoblastoid cell lines from these patients show reduced occupancy of regulatory regions and small changes in gene expression at a subset of genes associated with YY1 binding (Gabriele et al, 2017). These results are consistent with the model we describe for YY1 in global enhancer-promoter structuring, and with the idea that higher neurological functions are especially sensitive to such gene dysregulation.…”

Section: Discussionmentioning

confidence: 99%

YY1 Is a Structural Regulator of Enhancer-Promoter Loops

Weintraub

Zamudio

et al. 2017

Cell

773

808

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SUMMARY There is considerable evidence that chromosome structure plays important roles in gene control, but we have limited understanding of the proteins that contribute to structural interactions between gene promoters and their enhancer elements. Large DNA loops that encompass genes and their regulatory elements depend on CTCF-CTCF interactions, but most enhancer-promoter interactions do not employ this structural protein. Here, we show that the ubiquitously expressed transcription factor Yin Yang 1 (YY1) contributes to enhancer-promoter structural interactions in a manner analogous to DNA interactions mediated by CTCF. YY1 binds to active enhancers and promoter-proximal elements and forms dimers that facilitate the interaction of these DNA elements. Deletion of YY1 binding sites or depletion of YY1 protein disrupts enhancer-promoter looping and gene expression. We propose that YY1-mediated enhancer-promoter interactions are a general feature of mammalian gene control.

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Section: Discussionmentioning

confidence: 99%

YY1 Is a Structural Regulator of Enhancer-Promoter Loops

Weintraub

Zamudio

et al. 2017

Cell

773

808

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“…Haploinsufficiency of SIN3A causes a recognizable ID syndrome with a subset of the individuals displaying ASD, seizures, microcephaly and short stature [94]. Also, pathogenic variants in the RLIMinteracting protein YY1, a zinc finger transcription factor, which is implicated in the regulation of XCI [2] in mice, cause a syndromic form of ID with behavioral disturbances, intrauterine growth restriction, and various congenital malformations, through dysregulation of key transcriptional regulators [95]. These findings could hint at RLIM-NPAS3, RLIM-SIN3A, and RLIM-YY1 co-regulatory functions that, when impaired by genetic mutations, lead to clinically overlapping neurodevelopmental disorders.…”

Section: Discussionmentioning

confidence: 99%

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

et al. 2018

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RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes cosegregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

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“…We note that a very similar distribution of variants was recently documented for the YY1 gene (OMIM# 600013), which also encodes for a transcription factor with four C2H2‐type zinc fingers. Strikingly, the missense variants in the YY1 gene that cause intellectual disability, also appear to cluster in the zinc finger domains, with different variants affecting the identical amino acid residue (Gabriele et al., ). Mutational clustering in the ZNF region is described for ZBTB20 (OMIM# 606025) as well, where de novo variants in the C2H2 ZNF domain of this protein lead to a hypothyroidism phenotype (Mattioli et al., ).…”

Section: Discussionmentioning

confidence: 99%

Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene

Schoot

Munnik

Venselaar

et al. 2018

Molec Gen & Gen Med

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BackgroundPatients with pathogenic variants in ZBTB18 present with Intellectual Disability (ID) with frequent co‐occurrence of corpus callosum (CC) anomalies, hypotonia, microcephaly, growth problems and variable facial dysmorphologies. These features illustrate a key role for ZBTB18 in brain development.MethodsPatients with a pathogenic variant in ZBTB18 were detected by diagnostic whole exome sequencing (WES) performed in our center. We reviewed the literature and used GeneMatcher to include other cases. YASARA and WHAT IF were used to provide insight into the structural effect of missense variants located in the C2H2 zinc finger domains of the ZBTB18 protein.ResultsWe give a complete overview of pathogenic variants in ZBTB18 detected to date, showing inconsistent presence of clinical features, including CC anomalies. We present four new cases with a de novo pathogenic variant in the ZBTB18 gene, including the fourth case in which a de novo p.Arg464His variant was found.ConclusionHomology modeling of protein structure points to a variable degree of impaired DNA binding caused by missense variants in these domains probably leading to Loss of Function (LoF). Putative partial LoF may present with a less distinctive phenotype than complete LoF, as seen in truncating variants, which presents with an extensive variability in the phenotypic spectrum. Our data do not support a clear genotype to phenotype correlation.

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YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction

Cited by 126 publications

References 81 publications

YY1 Is a Structural Regulator of Enhancer-Promoter Loops

YY1 Is a Structural Regulator of Enhancer-Promoter Loops

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene

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