TY - JOUR
T1 - Heterozygous De Novo UBTF Gain-of-Function Variant Is Associated with Neurodegeneration in Childhood
AU - Edvardson, Simon
AU - Nicolae, Claudia M.
AU - Agrawal, Pankaj B.
AU - Mignot, Cyril
AU - Payne, Katelyn
AU - Prasad, Asuri Narayan
AU - Prasad, Chitra
AU - Sadler, Laurie
AU - Nava, Caroline
AU - Mullen, Thomas E.
AU - Begtrup, Amber
AU - Baskin, Berivan
AU - Powis, Zöe
AU - Shaag, Avraham
AU - Keren, Boris
AU - Moldovan, George Lucian
AU - Elpeleg, Orly
N1 - Publisher Copyright:
© 2017 American Society of Human Genetics
PY - 2017/8/3
Y1 - 2017/8/3
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2017.07.002
DO - 10.1016/j.ajhg.2017.07.002
M3 - Article
C2 - 28777933
AN - SCOPUS:85026438711
SN - 0002-9297
VL - 101
SP - 267
EP - 273
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -