RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation

Bustos, Francisco; Segarra-Fas, Anna; Chaugule, Viduth K.; Brandenburg, Lennart; Branigan, Emma; Toth, Rachel; Macartney, Thomas; Knebel, Axel; Hay, Ronald T.; Walden, Helen; Findlay, Greg M.

doi:10.1016/j.celrep.2018.04.022

Cited by 34 publications

(87 citation statements)

References 41 publications

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“…Enriched within the cohort of mRNAs suppressed by RNF12 re-expression are those with GO terms associated with neuronal ( Figure 5D) and neural ( Figure S5B) development, differentiation and function. This is consistent with a key function of RNF12 in restricting mESC differentiation to neurons (Bustos et al, 2018).…”

Section: Rnf12 E3 Ubiquitin Ligase Activity Controls a Neurodevelopmesupporting

confidence: 88%

“…RNF12 mutations cause an X-linked neurodevelopmental disorder termed Tonne-Kalscheuer Syndrome (TOKAS) (Frints et al, 2018;Hu et al, 2016;Tonne et al, 2015), which is underpinned by impaired RNF12 E3 ubiquitin ligase activity resulting in deregulated neuronal differentiation (Bustos et al, 2018). Thus, we hypothesised that SRPK phosphorylates and regulates RNF12, which may represent functional diversification of SRPKs in developmental signalling.…”

Section: Identification Of Srpk Substrates and Functions In Embryonicmentioning

confidence: 99%

“…complex that controls RNA PolII and stem cell pluripotency (Ding et al, 2009;Ponnusamy et al, 2009), and TJP2/ZO-2, a component of tight junctions. Also in this dataset is RNF12/RLIM, a RING-type E3 ubiquitin ligase, which ubiquitylates substrates for proteasomal degradation to control key developmental processes including imprinted X-chromosome inactivation (Shin et al, 2014), and stem cell maintenance and differentiation (Bustos et al, 2018;Zhang et al, 2012).…”

Section: Identification Of Srpk Substrates and Functions In Embryonicmentioning

confidence: 99%

“…We then sought to determine the mechanism by which RNF12 SR-motif phosphorylation stimulates catalytic activity. The SR-motif resides in a region proximal to a basic region implicated in the RNF12 catalytic mechanism (Bustos et al, 2018). Therefore, we investigated the impact of SR-motif phosphorylation on RNF12-dependent discharge of ubiquitin from a loaded E2 conjugating enzyme onto free lysine.…”

Section: Rnf12 Sr-motif Phosphorylation By Srpk Stimulates E3 Ubiquitmentioning

confidence: 99%

“…As SRPK-dependent phosphorylation of the RNF12 SR-motif activates and anchors RNF12 in the nucleus to promote degradation of transcription factor substrates such as REX1, we sought to identify the gene expression network that is regulated by this emergent signalling pathway. To this end, we employed RNF12-deficient mESCs (Rlim -/y ) (Bustos et al, 2018) reconstituted with either wild-type RNF12 or an E3 ubiquitin ligase catalytic mutant (W576Y), and performed RNA sequencing (RNA-SEQ) to identify genes that are specifically regulated by RNF12. As an initial validation of this experimental system, we show that degradation of REX1 substrate is restored by wild-type RNF12, but not RNF12 W576Y ( Figure 5A).…”

Section: Rnf12 E3 Ubiquitin Ligase Activity Controls a Neurodevelopmementioning

confidence: 99%

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Functional diversification of Ser-Arg rich protein kinases to control ubiquitin-dependent neurodevelopmental signalling

Bustos

Segarra-Fas

Nardocci

et al. 2020

Preprint

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Conserved protein kinases with core cellular functions have been frequently redeployed during metazoan evolution to regulate specialized developmental processes. Ser-Arg Repeat Protein Kinase (SRPK) is one such conserved eukaryotic kinase, which controls mRNA splicing.Surprisingly, we show that SRPK has acquired a novel function in regulating a neurodevelopmental ubiquitin signalling pathway. In mammalian embryonic stem cells, SRPK phosphorylates Ser-Arg motifs in RNF12/RLIM, a key developmental E3 ubiquitin ligase that is mutated in an intellectual disability syndrome. Processive phosphorylation by SRPK stimulates RNF12-dependent ubiquitylation of transcription factor substrates, thereby acting to restrain a neural gene expression programme that is aberrantly expressed in intellectual disability. SRPK family genes are also mutated in intellectual disability disorders, and patient-derived SRPK point mutations impair RNF12 phosphorylation. Our data reveal unappreciated functional diversification of SRPK to regulate ubiquitin signalling that ensures correct regulation of neurodevelopmental gene expression. 1998), suggesting that these protein kinases may indeed perform specialized functions required for multicellular development.Here, we show that SRPKs have undergone functional diversification to acquire a critical new role during mammalian development. Surprisingly, SRPK activity is largely dispensable for phosphorylation of Ser-Arg rich splicing factors (SRSFs) in mammalian embryo-derived stem cells.

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Section: Rnf12 E3 Ubiquitin Ligase Activity Controls a Neurodevelopmesupporting

confidence: 88%

Section: Identification Of Srpk Substrates and Functions In Embryonicmentioning

confidence: 99%

Section: Identification Of Srpk Substrates and Functions In Embryonicmentioning

confidence: 99%

Section: Rnf12 Sr-motif Phosphorylation By Srpk Stimulates E3 Ubiquitmentioning

confidence: 99%

Section: Rnf12 E3 Ubiquitin Ligase Activity Controls a Neurodevelopmementioning

confidence: 99%

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Functional diversification of Ser-Arg rich protein kinases to control ubiquitin-dependent neurodevelopmental signalling

Bustos

Segarra-Fas

Nardocci

et al. 2020

Preprint

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Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders

Hogg,

Findlay

2023

FEBS Letters

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Human developmental disorders encompass a wide range of debilitating physical conditions and intellectual disabilities. Perturbation of protein kinase signalling underlies the development of some of these disorders. For example, disrupted SRPK signalling is associated with intellectual disabilities, and the gene dosage of DYRKs can dictate the pathology of disorders including Down's syndrome. Here, we review the emerging roles of the CMGC kinase families SRPK, CLK, DYRK, and sub‐family HIPK during embryonic development and in developmental disorders. In particular, SRPK, CLK, and DYRK kinase families have key roles in developmental signalling and stem cell regulation, and can co‐ordinate neuronal development and function. Genetic studies in model organisms reveal critical phenotypes including embryonic lethality, sterility, musculoskeletal errors, and most notably, altered neurological behaviours arising from defects of the neuroectoderm and altered neuronal signalling. Further unpicking the mechanisms of specific kinases using human stem cell models of neuronal differentiation and function will improve our understanding of human developmental disorders and may provide avenues for therapeutic strategies.

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RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features

Palmer

Carroll

Shaw

et al. 2020

The American Journal of Human Genetics

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Interpretation of the significance of maternally inherited X chromosome variants in males with neurocognitive phenotypes continues to present a challenge to clinical geneticists and diagnostic laboratories. Here we report 14 males from 9 families with duplications at the Xq13.2-q13.3 locus with a common facial phenotype, intellectual disability (ID), distinctive behavioral features, and a seizure disorder in two cases. All tested carrier mothers had normal intelligence. The duplication arose de novo in three mothers where grandparental testing was possible. In one family the duplication segregated with ID across three generations. RLIM is the only gene common to our duplications. However, flanking genes duplicated in some but not all the affected individuals included the brain-expressed genes NEXMIF, SLC16A2, and the long non-coding RNA gene FTX. The contribution of the RLIM-flanking genes to the phenotypes of individuals with different size duplications has not been fully resolved. Missense variants in RLIM have recently been identified to cause X-linked ID in males, with heterozygous females typically having normal intelligence and highly skewed X chromosome inactivation. We detected consistent and significant increase of RLIM mRNA and protein levels in cells derived from seven affected males from five families with the duplication. Subsequent analysis of MDM2, one of the targets of the RLIM E3 ligase activity, showed consistent downregulation in cells from the affected males. All the carrier mothers displayed normal RLIM mRNA levels and had highly skewed X chromosome inactivation. We propose that duplications at Xq13.2-13.3 including RLIM cause a recognizable but mild neurocognitive phenotype in hemizygous males.

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RNF12 X-Linked Intellectual Disability Mutations Disrupt E3 Ligase Activity and Neural Differentiation

Cited by 34 publications

References 41 publications

Functional diversification of Ser-Arg rich protein kinases to control ubiquitin-dependent neurodevelopmental signalling

Functional diversification of Ser-Arg rich protein kinases to control ubiquitin-dependent neurodevelopmental signalling

Functions of SRPK, CLK and DYRK kinases in stem cells, development, and human developmental disorders

RLIM Is a Candidate Dosage-Sensitive Gene for Individuals with Varying Duplications of Xq13, Intellectual Disability, and Distinct Facial Features

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