Childhood neurodegeneration associated with a specific UBTF variant: a new case report and review of the literature

Bastos, Filipa; Quinodoz, Mathieu; Addor, Marie‐Claude; Royer‐Bertrand, Béryl; Fodstad, Heidi; Rivolta, Carlo; Poloni, Claudia; Superti‐Furga, Andrea; Roulet-Perez, Eliane; Lebon, Sébastien

doi:10.1186/s12883-019-1586-x

Cited by 17 publications

(35 citation statements)

References 13 publications

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“…A variant of UBTF encoding another transcription factor of Pol I (UBF) has recently been associated with neurodegenerative disease in children 3‐6 . The main clinical features were highly similar to the phenotype of the patients in this study (Table 1).…”

Section: Discussionsupporting

confidence: 68%

“…A variant of UBTF encoding another transcription factor of Pol I (UBF) has recently been associated with neurodegenerative disease in children. [3][4][5][6] The main clinical features were highly similar to the phenotype of the patients in this study (Table 1). After being initially normal, brain MRI of Patient 1 showed white matter hyperintensities in T2-weighted images, thinning of the corpus callosum, and diffuse brain atrophy ( Figure 2) which have also been reported with the UBTF variant.…”

Section: Molecular Genetic Studiessupporting

confidence: 54%

“…SL1 is a complex formed by TATA‐binding protein (TBP, MIM 600075) and three Pol I‐specific TBP‐associated factors (TAFs) 2 . Recently, a variant of UBTF leading to gain‐of‐function of UBF has been reported to cause altered rRNA metabolism and a pediatric neurodevelopmental disorder 3‐6 . The clinical picture is characterized by developmental regression and brain atrophy leading to microcephaly.…”

Section: Introductionmentioning

confidence: 99%

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Homozygous TAF1C variants are associated with a novel childhood‐onset neurological phenotype

et al. 2020

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TATA-box binding protein associated factor, RNA polymerase I subunit C (TAF1C) is a component of selectivity factor 1 belonging to RNA polymerase I (Pol I) transcription machinery. We report two unrelated patients with homozygous TAF1C missense variants and an early onset neurological phenotype with severe global developmental delay. Clinical features included lack of speech and ambulation and epilepsy. MRI of the brain demonstrated widespread cerebral atrophy and frontal periventricular white matter hyperintensity. The phenotype resembled that of a previously described variant of UBTF, which encodes another transcription factor of Pol I. TAF1C variants were located in two conserved amino acid positions and were predicted to be deleterious. In patient-derived fibroblasts, TAF1C mRNA and protein expression levels were substantially reduced compared with healthy controls. We propose that the variants impairing TAF1C expression are likely pathogenic and relate to a novel neurological disease. This study expands the disease spectrum related to Pol I transcription machinery, associating the TAF1C missense variants with a severe neurological phenotype for the first time.

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Section: Discussionsupporting

confidence: 68%

Section: Molecular Genetic Studiessupporting

confidence: 54%

Section: Introductionmentioning

confidence: 99%

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Homozygous TAF1C variants are associated with a novel childhood‐onset neurological phenotype

et al. 2020

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“…An E>K mutation at residue 210 in HMGbox2 of Ubtf was recently shown to be the cause of a recurrent human pediatric neuroregression syndrome (6,(11)(12)(13). The key role of HMGbox2 revealed by our study suggested that this mutation might affect the formation of the RPI preinitiation complex in vivo and possibly explain the origin of this syndrome.…”

Section: An Hmgbox2 Mutation Linked To Neuroregression Potentially Affects Ubtf Interactionsmentioning

confidence: 54%

“…Here we show that despite having little or no inherent DNA sequence selectivity, the multi-HMGbox Upstream Binding Factor (UBF/UBTF) plays a crucial role in targeting RPI preinitiation complex formation to the rDNA promoters in vivo. Further, we show that this UBTF function is compromised by an E210K mutation recently linked to a recurrent human pediatric neuroregression syndrome (6,(11)(12)(13).…”

Section: Introductionmentioning

confidence: 67%

Bidirectional cooperation between Ubtf1 and SL1 determines RNA Polymerase I promoter recognition in cell and is negatively affected in the UBTF-E210K neuroregression syndrome

Tremblay¹,

Sibai

Valere

et al. 2021

Preprint

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Transcription of the ~200 mouse and human ribosomal RNA genes (rDNA) by RNA Polymerase I (RPI/PolR1) accounts for 80% of total cellular RNA, around 35% of all nuclear RNA synthesis, and determines the cytoplasmic ribosome complement. It is therefore a major factor controlling cell growth and its misfunction has been implicated in hypertrophic and developmental disorders. Activation of each rDNA repeat requires nucleosome replacement by the architectural multi-HMGbox factor UBTF to create a 15kbp nucleosome free region (NFR). Formation of this NFR is also essential for recruitment of the TBP-TAF I factor SL1 and for preinitiation complex (PIC) formation at the gene and enhancer-associated promoters of the rDNA. However, these promoters show little sequence commonality and neither UBTF nor SL1 display significant DNA sequence binding specificity, making what drives PIC formation a mystery. Here we show that cooperation between SL1 and the longer UBTF1 splice variant generates the specificity required for rDNA promoter recognition in cell . We find that conditional deletion of the Taf1b subunit of SL1 causes a striking depletion UBTF at both rDNA promoters but not elsewhere across the rDNA. We also find that while both UBTF1 and -2 variants bind throughout the rDNA NFR, only UBTF1 is present with SL1 at the promoters. The data strongly suggest an induced-fit model of RPI promoter recognition in which UBTF1 plays an architectural role. Interestingly, a recurrent UBTF-E210K mutation and the cause of a pediatric neurodegeneration syndrome provides indirect support for this model. E210K knock-in cells show enhanced levels of the UBTF1 splice variant and a concomitant increase in active rDNA copies. In contrast, they also display reduced rDNA transcription and promoter recruitment of SL1. We suggest the underlying cause of the UBTF-E210K syndrome is therefore a reduction in cooperative UBTF1-SL1 promoter recruitment that may be partially compensated by enhanced rDNA activation.

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A novel, likely pathogenic variant in UBTF‐related neurodegeneration with brain atrophy is associated with a severe divergent neurodevelopmental phenotype

Tinker

Guess

Rinker

et al. 2022

Molec Gen & Gen Med

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Background: A de novo, pathogenic, missense variant in UBTF, c.628G>A p.Glu210Lys, has been described as the cause of an emerging neurodegenerative disorder, Childhood-Onset Neurodegeneration with Brain Atrophy (CONDBA).The p.Glu210Lys alteration yields a positively charged stretch of three lysine residues. Functional studies confirmed this change results in a stronger interaction with negatively charged DNA and gain-of-function activity when compared to the wild-type sequence. The CONDBA phenotype reported in association with p.Glu210Lys consists of normal early-neurodevelopment followed by progressive motor, cognitive, and behavioral regression in early-to-middle childhood. Methods and Results:The current proband presented at 9 months of age with baseline developmental delay and more extensive neuroradiological findings, including pontine hypoplasia, thalamic volume loss and signal abnormality, and hypomyelination. Like the recurrent CONDBA p.Glu210Lys variant, this novel variant, c.608A>G p.(Gln203Arg) lies within the highly conserved second HMGbox homology domain and involves the replacement of the wild-type residue with a positively charged residue, arginine. Computational structural modeling demonstrates that this amino acid substitution potentiates the interaction between UBTF and DNA, likely resulting in a gain-of-function effect for the UBTF protein, UBF. Conclusion:Here we present a new divergent phenotype associated with a novel, likely pathogenic, missense variant at a different position in the UBTF gene, c.608A>G p.(Gln203Arg).

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Childhood neurodegeneration associated with a specific UBTF variant: a new case report and review of the literature

Cited by 17 publications

References 13 publications

Homozygous TAF1C variants are associated with a novel childhood‐onset neurological phenotype

Homozygous TAF1C variants are associated with a novel childhood‐onset neurological phenotype

Bidirectional cooperation between Ubtf1 and SL1 determines RNA Polymerase I promoter recognition in cell and is negatively affected in the UBTF-E210K neuroregression syndrome

A novel, likely pathogenic variant in UBTF‐related neurodegeneration with brain atrophy is associated with a severe divergent neurodevelopmental phenotype

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