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

TitleHeterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood.
Publication TypeJournal Article
Year of Publication2017
AuthorsEdvardson, S, Nicolae, CM, Agrawal, PB, Mignot, C, Payne, K, Prasad, ANarayan, Prasad, C, Sadler, L, Nava, C, Mullen, TE, Begtrup, A, Baskin, B, Powis, Z, Shaag, A, Keren, B, Moldovan, G-L, Elpeleg, O
JournalAm J Hum Genet
Date Published2017 Aug 03
KeywordsAdolescent, Adult, Atrophy, Brain, Brain Diseases, Cell Nucleolus, Child, Chromatin, DNA-Binding Proteins, Female, Humans, Male, Neurodegenerative Diseases, Pol1 Transcription Initiation Complex Proteins, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, RNA, Ribosomal, 18S, Young Adult

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.

Alternate JournalAm. J. Hum. Genet.
PubMed ID28777933
PubMed Central IDPMC5544390
Grant ListR01 AR068429 / AR / NIAMS NIH HHS / United States
U19 HD077671 / HD / NICHD NIH HHS / United States
UM1 HG008900 / HG / NHGRI NIH HHS / United States