2. Academic Validation
  3. Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood

Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood

  • Am J Hum Genet. 2017 Aug 3;101(2):267-273. doi: 10.1016/j.ajhg.2017.07.002.
Simon Edvardson 1,  Claudia M Nicolae 2,  Pankaj B Agrawal 3,  Cyril Mignot 4,  Katelyn Payne 5,  Asuri Narayan Prasad 6,  Chitra Prasad 7,  Laurie Sadler 8,  Caroline Nava 9,  Thomas E Mullen 10,  Amber Begtrup 11,  Berivan Baskin 11,  Zöe Powis 12,  Avraham Shaag 13,  Boris Keren 4,  George-Lucian Moldovan 14,  Orly Elpeleg 15
Affiliations

Affiliations

  • 1 Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; Pediatric Neurology Unit, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
  • 2 Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA.
  • 3 Divisions of Newborn Medicine and Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 4 Département de Génétique, APHP, GH Pitié-Salpêtrière, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Paris 75013, France.
  • 5 Riley Hospital for Children, Indianapolis, Indiana, IN, 46202, USA.
  • 6 Section of Paediatric Neurology, Department of Paediatrics, and the Division of Clinical Neurological Sciences, Faculty of Medicine, Schulich School of Medicine and Dentistry, Western University, London, Ontario N6A 3K7, Canada.
  • 7 Department of Paediatrics, Section of Genetics, Western University London Ontario N6A 3K7, Canada.
  • 8 Division of Genetics, Department of Pediatrics, Women and Children's Hospital of Buffalo, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, State University of New York, Buffalo, NY 14214, USA.
  • 9 Département de Génétique, APHP, GH Pitié-Salpêtrière, Centre de Référence des Déficiences Intellectuelles de Causes Rares, Paris 75013, France; INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, 75013, Paris, France.
  • 10 Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, 53377, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA 02142 USA.
  • 11 GeneDx, Gaithersburg, MD 20877, USA.
  • 12 Department of Emerging Genetic Medicine, Ambry Genetics, Aliso Viejo, California, USA 92656.
  • 13 Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
  • 14 Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA. Electronic address: gmoldovan@pennstatehealth.psu.edu.
  • 15 Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. Electronic address: elpeleg@hadassah.org.il.
PMID: 28777933 DOI: 10.1016/j.ajhg.2017.07.002
Abstract

Ribosomal RNA (rRNA) is transcribed from rDNA by RNA polymerase I (Pol I) to produce the 45S precursor of the 28S, 5.8S, and 18S rRNA components of the ribosome. Two transcription factors have been defined for Pol I in mammals, the selectivity factor SL1, and the upstream binding transcription factor (UBF), which interacts with the upstream control element to facilitate the assembly of the transcription initiation complex including SL1 and Pol I. In seven unrelated affected individuals, all suffering from developmental regression starting at 2.5-7 years, we identified a heterozygous variant, c.628G>A in UBTF, encoding p.Glu210Lys in UBF, which occurred de novo in all cases. While the levels of UBF, Ser388 phosphorylated UBF, and other Pol I-related components (POLR1E, TAF1A, and TAF1C) remained unchanged in cells of an affected individual, the variant conferred gain of function to UBF, manifesting by markedly increased UBF binding to the rDNA promoter and to the 5'- external transcribed spacer. This was associated with significantly increased 18S expression, and enlarged nucleoli which were reduced in number per cell. The data link neurodegeneration in childhood with altered rDNA chromatin status and rRNA metabolism.

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