A recurrent de novo missense mutation in UBTF causes developmental neuroregression

Abstract

UBTF (upstream binding transcription factor) exists as two isoforms; UBTF1 regulates rRNA transcription by RNA polymerase 1, whereas UBTF2 regulates mRNA transcription by RNA polymerase 2. Herein, we describe 4 patients with very similar patterns of neuroregression due to recurrent de novo mutations in UBTF (GRCh37/hg19, NC_000017.10: g.42290219C > T, NM_014233.3: c.628G > A) resulting in the same amino acid change in both UBTF1 and UBTF2 (p.Glu210Lys [p.E210K]). Disease onset in our cohort was at 2.5 to 3 years and characterized by slow progression of global motor, cognitive and behavioral dysfunction. Notable early features included hypotonia with a floppy gait, high-pitched dysarthria and hyperactivity. Later features included aphasia, dystonia, and spasticity. Speech and ambulatory ability were lost by the early teens. Magnetic resonance imaging showed progressive generalized cerebral atrophy (supratentorial > infratentorial) with involvement of both gray and white matter. Patient fibroblasts showed normal levels of UBTF transcripts, increased expression of pre-rRNA and 18S rRNA, nucleolar abnormalities, markedly increased numbers of DNA breaks, defective cell-cycle progression, and apoptosis. Expression of mutant human UBTF1 in Drosophila neurons was lethal. Although no loss-of-function variants are reported in the Exome Aggregation Consortium (ExAC) database and Ubtf−/− is early embryonic lethal in mice, Ubtf+/− mice displayed only mild motor and behavioral dysfunction in adulthood. Our data underscore the importance of including UBTF E210K in the differential diagnosis of neuroregression and suggest that mainly gain-of-function mechanisms contribute to the pathogenesis of the UBTF E210K neuroregression syndrome.

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

“…The literature search yielded two case series and a case report of patients carrying the same de novo heterozygous c.628G>A UBTF variant [1][2][3]. Results are summarised in Table 1.…”

“…Recently three independent teams [1][2][3] reported on a new monogenic neurodegenerative disease of childhood associated with a specific monoallelic de novo c.628G>A (p.Glu210Lys) UBTF variant. Together, 12 male and female patients aged 6 to 33 years old were described with a consistent phenotype of normal or close to normal early developmental milestones followed by motor and cognitive regression [1][2][3].…”

“…UBTF (Upstream Binding Transcription Factor, OMIM *600673) gene codes for Upstream Binding Factor (UBF), a protein that acts as a transcription factor for RNA polymerase I, essential for the generation of ribosomal RNA transcripts (rRNA) from ribosomal DNA (rDNA) in the nucleolus [1,2]. The c.628G>A variant confers a gain of function to the protein resulting in increased expression of rDNA and rRNA, which in turn is thought to lead to scavenging of RNA binding proteins, altered RNA disposal machinery and ribosome biogenesis [1], as well as defective DNA damage repair and chromatid cohesion [1,2,4,5].…”

UBTF Mutation Causes Complex Phenotype of Neurodegeneration and Severe Epilepsy in Childhood

“…UBTF gene was not yet associated with any human disease at that time. This variant was not included in global/population databases such as the 1,000 Genome project (www.internationalgenome.org), Exome Aggregation Consortium (http://exac.broadinstitute.org), or Exome Variant Server (http://evs.gs.washington.edu/EVS) until recently reported in association with neurodegeneration 3,4 and eventually entered in the Human Gene Mutation Database (HGMD, Cardiff University, Cardiff, Wales, UK) Professional database (www.hgmd.cf.ac.uk).…”

“…A further four patients were described with very similar neurodegeneration also due to the same recurrent de novo variant c.628G > A. 4 This is the only known pathogenic mutation in this gene. Here we describe another patient who is older than most other reported patients suffering from severe progressive neurodegeneration and in whom we have identified the same unique heterozygous de novo variant by whole exome sequencing (WES).…”