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Hum Mol Genet. 2018 Feb 15;27(4):691-705. doi: 10.1093/hmg/ddx435.

A recurrent de novo missense mutation in UBTF causes developmental neuroregression.

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Undiagnosed Diseases Program and Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA.
Division of Child Neurology, Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA.
Integrated Program in Biological Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA.
Laboratory of Growth and Development, St-Patrick Research Group in Basic Oncology, Cancer Division of the Quebec University Hospital Research Centre, Canada.
Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, QC, Canada.
Center for Rare Childhood Disorders (C4RCD), Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.


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.

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