Genetic variants in the <i>KDM6B</i> gene are associated with neurodevelopmental delays and dysmorphic features

Stolerman, Elliot; Francisco, E. Nicolás; Stallworth, Jennifer L.; Jones, Julie R.; Monaghan, Kristin G.; Keller‐Ramey, Jennifer; Person, Richard; Wentzensen, Ingrid M.; McWalter, Kirsty; Keren, Boris; Héron, Bénédicte; Nava, Caroline; Héron, Delphine; Kim, Katherine; Burton, Barbara K.; Almusafri, Fatima; O’Grady, Lauren; Sahai, Inderneel; Escobar, Luis; Meuwissen, Marije; Reyniers, Edwin; Kooy, R. Frank; Lacassie, Yves; Gunay‐Aygun, Meral; Schatz, Krista Sondergaard; Hochstenbach, Ron; Zwijnenburg, Petra J.G.; Waisfisz, Quinten; Slegtenhorst, Marjon van; Mancini, Grazia M.S.; Louie, Raymond J.

doi:10.1002/ajmg.a.61173

Cited by 43 publications

(43 citation statements)

References 27 publications

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“…Notably, de novo loss-of-function variants in KDM6B cause a neurodevelopmental syndrome that has phenotypic overlap with RFX3 haploinsufficiency as described in this report, namely mild global delays, delayed speech, hypotonia, and features of ASD and ADHD, while loss-of-function variants in NONO and MYT1L are a cause of X-linked and autosomal dominant intellectual disability, respectively (Table S4). 48–55 These cases support the model that RFX members may be transcriptional activators of a subset of ASD risk genes via actions at both enhancer and promoter sites.…”

Section: Resultssupporting

confidence: 62%

Disruption of RFX family transcription factors causes autism, attention deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Harris

Nakayama

Lai

et al. 2020

Preprint

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Purpose: We describe a novel neurobehavioral syndrome of autism spectrum disorder, intellectual disability, and attention deficit/hyperactivity disorder associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. Methods: We assembled a cohort of 36 individuals (from 31 unrelated families) with de novo mutations in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. Results: These individuals share neurobehavioral features including autism spectrum disorder (ASD), intellectual disability, and attention-deficit/hyperactivity disorder (ADHD); other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. Conclusion: These results establish deleterious variation in RFX3, RFX4, and RFX7 as important causes of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.

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Section: Resultssupporting

confidence: 62%

Disruption of RFX family transcription factors causes autism, attention deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Harris

Nakayama

Lai

et al. 2020

Preprint

View full text Add to dashboard Cite

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“…Additionally, cytoplasmic vacuole formation and apoptosis-related genes were significantly highly expressed in these cell types after RGNNV infection. For example, lysine (K)-specific demethylase 6B (Kdm6b) was the most important gene involved in the induction of neuro-dysmorphia and it promotes cell apoptosis [74,75]. Furthermore, rho-GTPase activating protein 6 (Arhgap6) is an important gene for cytoskeleton rearrangements and may play an important role in cytoplasmic vacuole formation [76].…”

Section: Plos Pathogensmentioning

confidence: 99%

Single-cell RNA-seq landscape midbrain cell responses to red spotted grouper nervous necrosis virus infection

et al. 2021

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Viral nervous necrosis (VNN) is an acute and serious fish disease caused by nervous necrosis virus (NNV) which has been reported massive mortality in more than fifty teleost species worldwide. VNN causes damage of necrosis and vacuolation to central nervous system (CNS) cells in fish. It is difficult to identify the specific type of cell targeted by NNV, and to decipher the host immune response because of the functional diversity and highly complex anatomical and cellular composition of the CNS. In this study, we found that the red spotted grouper NNV (RGNNV) mainly attacked the midbrain of orange-spotted grouper (Epinephelus coioides). We conducted single-cell RNA-seq analysis of the midbrain of healthy and RGNNV-infected fish and identified 35 transcriptionally distinct cell subtypes, including 28 neuronal and 7 non-neuronal cell types. An evaluation of the subpopulations of immune cells revealed that macrophages were enriched in RGNNV-infected fish, and the transcriptional profiles of macrophages indicated an acute cytokine and inflammatory response. Unsupervised pseudotime analysis of immune cells showed that microglia transformed into M1-type activated macrophages to produce cytokines to reduce the damage to nerve tissue caused by the virus. We also found that RGNNV targeted neuronal cell types was GLU1 and GLU3, and we found that the key genes and pathways by which causes cell cytoplasmic vacuoles and autophagy significant enrichment, this may be the major route viruses cause cell death. These data provided a comprehensive transcriptional perspective of the grouper midbrain and the basis for further research on how viruses infect the teleost CNS.

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“…KDM4B (JMJD2B) and KDM6B (JMJD3) are two important histone demethylases [ 35 – 37 ]. Human JMJD3 or KDM6B (lysine-specific demethylase 6B) gene is located at 17p13.1 and encodes a polypeptide that contains 1682 amino acids with an average molecular weight of 176,632 Da [ 10 , 38 ]. JMJD3 belongs to a subfamily of the UTX/UTY JmjC-domain protein [ 12 ].…”

Section: Structure and Function Of Jmjd3mentioning

confidence: 99%

JMJD3: a critical epigenetic regulator in stem cell fate

et al. 2021

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The Jumonji domain-containing protein-3 (JMJD3) is a histone demethylase that regulates the trimethylation of histone H3 on lysine 27 (H3K27me3). H3K27me3 is an important epigenetic event associated with transcriptional silencing. JMJD3 has been studied extensively in immune diseases, cancer, and tumor development. There is a comprehensive epigenetic transformation during the transition of embryonic stem cells (ESCs) into specialized cells or the reprogramming of somatic cells to induced pluripotent stem cells (iPSCs). Recent studies have illustrated that JMJD3 plays a major role in cell fate determination of pluripotent and multipotent stem cells (MSCs). JMJD3 has been found to enhance self-renewal ability and reduce the differentiation capacity of ESCs and MSCs. In this review, we will focus on the recent advances of JMJD3 function in stem cell fate.

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Genetic variants in the KDM6B gene are associated with neurodevelopmental delays and dysmorphic features

Cited by 43 publications

References 27 publications

Disruption of RFX family transcription factors causes autism, attention deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Disruption of RFX family transcription factors causes autism, attention deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Single-cell RNA-seq landscape midbrain cell responses to red spotted grouper nervous necrosis virus infection

JMJD3: a critical epigenetic regulator in stem cell fate

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