UBTF

protein-coding

upstream binding transcription factor, the group of MicroRNA protein coding host genes

Gene summary

This gene encodes a member of the HMG-box DNA-binding protein family. The encoded protein plays a critical role in ribosomal RNA transcription as a key component of the pre-initiation complex, mediating the recruitment of RNA polymerase I to rDNA promoter regions. The encoded protein may also play important roles in chromatin remodeling and pre-rRNA processing, and its activity is regulated by both phosphorylation and acetylation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. Pseudogenes of this gene are located on the short arm of chromosomes 3, 11 and X and the long arm of chromosome 11. [provided by RefSeq, Aug 2011]

MANE transcript

NM_014233.4

Inheritance

ClinVar variants

P:7U:122B:20

Top phenotype

Neurodegeneration, childhood-onset, with brain atrophy

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr17:44,205,033-44,221,626

External References & Databases

Ensembl (ENSG00000108312)

Transcript & Mutation Effects

hg38 • Region Span ~16.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0044701

Submitter: ClinGen

*UBTF* was first reported in relation to autosomal dominant childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder in 2017 (Edvardson et al., PMID: 28777933). The phenotype consists of normal or mildly delayed early-neurodevelopment followed by progressive motor, cognitive, and behavioral regression in early-to-middle childhood (ranging from 2.5 to 7 years of age). Later features include profound intellectual disability, dysarthria progressing to aphasia, secondary microcephaly, spasticity, dystonia, gait ataxia, and loss of speech and ambulatory ability by the early teen years. Brain MRI shows progressive neurodegeneration, with cerebral and cerebellar atrophy, and involvement of both gray and white matter. A recurrent *de novo* missense variant, p.Glu210Lys (E210K), reported in 16 probands is included in this curation (PMIDs: 28777933, 29300972, 30517966, 31931739, 33026538, 36138999, 37162731). A different *de novo* missense variant was reported in a single proband with severe early-onset developmental delay and cerebral and cerebellar atrophy (PMID: 36106513); this variant has not been functionally validated and was not scored. *UBTF* encodes a transcriptional activator of ribosomal RNA (rRNA) expression. The mechanism of pathogenicity appears to be gain-of-function, as suggested by studies in patient fibroblasts with the p.Glu210Lys variant showing increased UBF binding to the ribosomal DNA (rDNA) promoter and increased expression of pre-rRNA and 18S rRNA (PMIDs: 28777933, 29300972). However, studies in fibroblasts from homozygous *Ubtf* E210K knock-in mice revealed reduced association between UBTF1 and the RNA polymerase I transcription factor SL1 at the rDNA promoter and this correlated with a reduced rate of pre-rRNA synthesis as determined by metabolic labeling, suggesting a loss-of-function mechanism (PMID: 35139074). Additional experiments are needed to clarify the disease mechanism for this condition. In summary, there is definitive evidence to support the relationship between *UBTF* and autosomal dominant childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on August 16, 2023 (SOP Version 9).

childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0044701

Submitter: Ambry Genetics

childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0044701

Submitter: PanelApp Australia

childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0044701

Submitter: Illumina

childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0044701

Submitter: Labcorp Genetics (formerly Invitae)

childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0044701

Submitter: G2P

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorderSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0044701

Submitter: Orphanet

Clinical Genomic Database (CGD)

Neurodegeneration, childhood-onset, with brain atrophyAD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 28777933

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UBTF variants in ClinVar

11 Conditions Cataloged

not providedTotal: 64

Inborn genetic diseasesTotal: 46

not specifiedTotal: 22

Childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorderTotal: 19

UBTF-related disorderTotal: 15

ObesityTotal: 1

Neurodevelopmental disorderTotal: 1

Rare syndromic intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014233.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	11 clinvar	5 clinvar	20
missense		2 clinvar	94 clinvar	4 clinvar		100
nonsense		3 clinvar	5 clinvar			8
start loss						0
frameshift		1 clinvar	6 clinvar			7
splice donor/acceptor (+/-2bp)		1 clinvar	13 clinvar			14
Total	0	7	122	15	5	149

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 171 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_014233.4	RefSeq	NP_055048.1	20	MANE Select
ENST00000436088.6	Ensembl	ENSP00000390669.1	20	MANE Select
NM_001076683.2	RefSeq	NP_001070151.1	19	Standard
NM_001076684.3	RefSeq	NP_001070152.1	19	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ectoderm Differentiation
NoRC negatively regulates rRNA expression
Negative epigenetic regulation of rRNA expression
Epigenetic regulation of gene expression
Gene expression (Transcription)

Biological Process

RNA polymerase I preinitiation complex assembly
regulation of transcription by RNA polymerase I
regulation of transcription by RNA polymerase II
transcription by RNA polymerase I
transcription initiation from RNA polymerase I promoter

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
RNA polymerase I CORE element sequence-specific DNA binding
RNA polymerase I upstream control element sequence-specific DNA binding
chromatin binding
RNA binding

Cellular Component

fibrillar center
nucleus
nucleoplasm
nucleolus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000302904
Coding exons: 20
Length: 16594
Individuals with no LoFs: 125659
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125660
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.75	172	458	0.376	0.0000277	5111
Missense (PolyPhen)		26	176.52	0.14729		1928
Synonymous	-1.42	210	185	1.13	0.0000122	1302
Loss of Function	6.55	0	49.9	0.00	0.00000258	571

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Recognizes the ribosomal RNA gene promoter and activates transcription mediated by RNA polymerase I through cooperative interactions with the transcription factor SL1/TIF-IB complex. It binds specifically to the upstream control element. {ECO:0000269|PubMed:28777933, ECO:0000269|PubMed:7982918}.;
Disease: DISEASE: Neurodegeneration, childhood-onset, with brain atrophy (CONDBA) [MIM:617672]: An autosomal dominant neurodegenerative disease with onset in childhood, characterized by progressive cortical atrophy, developmental delay, developmental regression, loss of motor skills and ambulation, absence of language, and intellectual disability. {ECO:0000269|PubMed:28777933}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.172

Intolerance Scores

LoFtool: 0.00537
RVIS EVS: -1.16
RVIS percentile EVS: 6.17

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.878

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium