2. Academic Validation
  3. A recurrent de novo missense mutation in UBTF causes developmental neuroregression

A recurrent de novo missense mutation in UBTF causes developmental neuroregression

  • Hum Mol Genet. 2018 Feb 15;27(4):691-705. doi: 10.1093/hmg/ddx435.
Camilo Toro 1,  Roderick T Hori 2,  May Christine V Malicdan 1,  Cynthia J Tifft 1,  Amy Goldstein 3,  William A Gahl 1,  David R Adams 1,  Harper B Fauni 1,  Lynne A Wolfe 1,  Jianfeng Xiao 4,  Mohammad M Khan 4,  Jun Tian 4,  Kevin A Hope 5,  Lawrence T Reiter 4 6,  Michel G Tremblay 7 8,  Tom Moss 7 8,  Alexis L Franks 3,  Chris Balak 9,  C4RCD Research Group,  Mark S LeDoux 4
Affiliations

Affiliations

  • 1 Undiagnosed Diseases Program and Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
  • 2 Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA.
  • 3 Division of Child Neurology, Department of Pediatrics, Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
  • 4 Departments of Neurology and Anatomy & Neurobiology, University of Tennessee Health Science Center, Memphis, TN, USA.
  • 5 Integrated Program in Biological Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
  • 6 Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA.
  • 7 Laboratory of Growth and Development, St-Patrick Research Group in Basic Oncology, Cancer Division of the Quebec University Hospital Research Centre, Canada.
  • 8 Department of Molecular Biology, Medical Biochemistry and Pathology, Faculty of Medicine, Laval University, QC, Canada.
  • 9 Center for Rare Childhood Disorders (C4RCD), Translational Genomics Research Institute (TGen), Phoenix, AZ, USA.
PMID: 29300972 DOI: 10.1093/hmg/ddx435
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.

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