A novel c.2T &gt; C mutation of the KDM5C/JARID1C gene in one large family with X-linked intellectual disability

Õunap, Katrin; Puusepp-Benazzouz, Helen; Peters, Maire; Vaher, Ulvi; Rein, Reet; Proos, Anné; Field, Mike; Reimand, Tiia

doi:10.1016/j.ejmg.2012.01.004

Cited by 38 publications

(37 citation statements)

References 23 publications

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“…All the affected siblings commonly show a prominent nasal bridge, diastema, and thin upper lip vermillion ( Fig. 1f-k and Table S1), as previously reported (11)(12)(13)(14).…”

Section: Resultssupporting

confidence: 80%

Different X-linkedKDM5Cmutations in affected male siblings: is maternal reversion error involved?

et al. 2016

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Genetic reversion is the phenomenon of spontaneous gene correction by which gene function is partially or completely rescued. However, it is unknown whether this mechanism always correctly repairs mutations, or is prone to error. We investigated a family of three boys with intellectual disability, and among them we identified two different mutations in KDM5C, located at Xp11.22, using whole-exome sequencing. Two affected boys have c.633delG and the other has c.631delC. We also confirmed de novo germline (c.631delC) and low-prevalence somatic (c.633delG) mutations in their mother. The two mutations are present on the same maternal haplotype, suggesting that a postzygotic somatic mutation or a reversion error occurred at an early embryonic stage in the mother, leading to switched KDM5C mutations in the affected siblings. This event is extremely unlikely to arise spontaneously (with an estimated probability of 0.39-7.5 × 10(-28) ), thus a possible reversion error is proposed here to explain this event. This study provides evidence for reversion error as a novel mechanism for the generation of somatic mutations in human diseases.

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“…All the affected siblings commonly show a prominent nasal bridge, diastema, and thin upper lip vermillion ( Fig. 1f-k and Table S1), as previously reported (11)(12)(13)(14).…”

Section: Resultssupporting

confidence: 80%

Different X-linkedKDM5Cmutations in affected male siblings: is maternal reversion error involved?

et al. 2016

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“…Interestingly, the XCI test showed a completely skewed inactivation pattern in all four affected female siblings, while the unaffected female sibling had a random XCI pattern. Work done by Ounap et al [2012] further supports our theory that XIS in Figure 3. Schematic representation of microexons in the KDM5/Kdm5 genes.…”

Section: Discussionsupporting

confidence: 76%

The potential role of a retrotransposed gene and a long noncoding RNA in regulating an X‐linked chromatin gene (KDM5C): Novel epigenetic mechanism in autism

2019

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A growing body of evidence supports the potential role of the circadian system and chromatin remodeling genes in autism. Considering the heterogeneity and gender discrepancy in autism, and the complex nature of the epigenetic landscape, identification of biologically relevant epigenetic factors requires reducing heterogeneity using proper subtyping. For this study, we used X chromosome inactivation (XCI) status in females with autism as an epigenetic marker for subtyping and examined the expression level of members of KDM5, a chromatin remodeling gene family. KDM5 are histone demethylases involved in the circadian molecular machinery. We used human blood samples to characterize alternatively spliced KDM5 isoforms and noticed that KDM5C undergoes a complex splicing process. We also identified a KDM5C isoform (KDM5C‐3′UTR‐lncRNA) containing a novel 3′UTR originated from a retrotransposed gene (retro‐SUV39H2) of an autosomal methyltransferase (SUV39H2). This 3′UTR shows 84% sequence homology with long ncRNAs (lncRNAs) and is located 32 kb downstream of KDM5C. The KDM5C‐3′UTR‐lncRNA isoform was differentially expressed in autistic females with XCI skewness compared with controls. KDM5C plays a crucial role in balancing histone H3K4 methylation states. The identified retro‐SUV39H2 originated lncRNA also shows H3K4 marks. By assessing the expression level of alternatively spliced Kdm5 isoforms at different circadian time‐points, we showed that some isoforms follow a circadian oscillation pattern in wild type mouse brain.This study provides the first evidence and a suggestive model for the potential role of retrotransposed elements in autism through linking methylases and demethylases, two functionally complementary components of chromatin remodeling, which may collectively contribute to disease etiology through lncRNAs. Autism Res 2019, 12: 1007–1021. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary Genes do not function in isolated conditions and their proper expression level also depends on a mechanism called gene regulation. An example of gene regulation is when changes outside DNA sequences influence the function of autism susceptibility genes. Alternative splicing is one type of gene regulation, which produces several versions of a gene (called variants) that may slightly differ from each other and be expressed at different levels in response to environmental changes. The circadian clock is an essential timing mechanism that enables organisms to maintain internal processes in sync with the dynamic environment brought about by the day–night cycle. The goal of this study was to assess if a subset of females with autism with certain genetic marker had a unique pattern of alternative splicing of three circadian genes. We identified a novel variant that is differentially expressed in this subset. Our study provides a novel subject stratification strategy, and a suggestive model of how biologically relevant components of a gene regulatory process may be linked and, possibly, collecti...

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“…Deletion of specific JmjC-KDMs in numerous developmental models results in embryonic lethality and future science group Review Hancock, Dunne, Walport, Flashman & Kawamura morphological defects [98][99][100]. Additionally, JmjC-KDM mutations have been linked to several developmental syndromes [103][104][105]. Various studies have linked each of the JmjC-KDM subfamilies to developmental roles (see Pedersen and Helin review [99]).…”

Section: Jmjc-kdms and Developmentmentioning

confidence: 99%

Epigenetic Regulation by Histone Demethylases in Hypoxia

et al. 2015

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The response to hypoxia is primarily mediated by the hypoxia-inducible transcription factor (HIF). Levels of HIF are regulated by the oxygen-sensing HIF hydroxylases, members of the 2-oxoglutarate (2OG) dependent oxygenase family. JmjC-domain containing histone lysine demethylases (JmjC-KDMs), also members of the 2OG oxygenase family, are key epigenetic regulators that modulate the methylation levels of histone tails. Kinetic studies of the JmjC-KDMs indicate they could also act in an oxygen-sensitive manner. This may have important implications for epigenetic regulation in hypoxia. In this review we examine evidence that the levels and activity of JmjC-KDMs are sensitive to oxygen availability, and consider how this may influence their roles in early development and hypoxic disease states including cancer and cardiovascular disease.

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A novel c.2T > C mutation of the KDM5C/JARID1C gene in one large family with X-linked intellectual disability

Cited by 38 publications

References 23 publications

Different X-linkedKDM5Cmutations in affected male siblings: is maternal reversion error involved?

Different X-linkedKDM5Cmutations in affected male siblings: is maternal reversion error involved?

The potential role of a retrotransposed gene and a long noncoding RNA in regulating an X‐linked chromatin gene (KDM5C): Novel epigenetic mechanism in autism

Epigenetic Regulation by Histone Demethylases in Hypoxia

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