GeneBe

HNRNPU

protein-coding

heterogeneous nuclear ribonucleoprotein U, the group of Heterogeneous nuclear ribonucleoproteins

Gene summary

This gene encodes a member of a family of proteins that bind nucleic acids and function in the formation of ribonucleoprotein complexes in the nucleus with heterogeneous nuclear RNA (hnRNA). The encoded protein has affinity for both RNA and DNA, and binds scaffold-attached region (SAR) DNA. Mutations in this gene have been associated with epileptic encephalopathy, early infantile, 54. A pseudogene of this gene has been identified on chromosome 14. [provided by RefSeq, Jun 2017]

Previous symbols:
  • HNRPU
  • HNRNPU-AS1
  • C1orf199
  • NCRNA00201

MANE transcript

NM_031844.3

Inheritance

AD, AR

ClinVar variants

P:167U:357B:413

Top phenotype

Developmental and epileptic encephalopathy 54

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr1:244,840,638-244,864,560

External References & Databases

Ensembl (ENSG00000153187)NCBI Gene (3192)OMIM (602869)HGNC:5048GenCCUniProt (Q00839)AlphaFoldClinVar (HNRNPU)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~23.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*HNRNPU* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2013 (Carvill et al., PMID: 237081887). This disease entity was named Developmental and Epileptic Encephalopathy type 54 (DEE54, OMIM #617391). To date, approximately 75 patients with heterozygous *HNRNPU* sequence variants have been published in the literature (Taylor et al., 2022, PMID: 35138025). Except where parental samples were not available, all probands had *de novo* variants. Commonly reported phenotypes include developmental delay, intellectual disability, seizures, non-specific dysmorphic features, hypotonia, feeding difficulties, short stature, behavioral issues, autism or autistic features, strabismus, abnormalities on brain MRI, cardiac defects, and renal anomalies. The majority of reported variants are frameshift, nonsense, and canonical splicing variants; a smaller number of missense and small in-frame deletions have been reported. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, we opted to lump into one disease entity, complex neurodevelopmental disorder. Six variants (2 nonsense and 4 frameshift, all *de novo*) that have been reported in 6 probands in 3 publications (PMIDs: 28393272, 35138025, 28944577) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Of note, the Brain Gene Registry includes 5 subjects with *de novo* *HNRNPU* variants, including one each of nonsense, frameshift, whole gene deletion, missense, and splicing variants (BGR study IDs: 110004101, 113017101, 110003101, 110017101, 104002101). The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence, including a mouse model and biochemical function (PMIDs: 35864088, 33874999). In summary, there is definitive evidence to support the relationship between *HNRNPU* and autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 10, 2022 (SOP Version 9).

developmental and epileptic encephalopathy, 54MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0033363

Submitter: Ambry Genetics

developmental and epileptic encephalopathy, 54STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033363

Submitter: Labcorp Genetics (formerly Invitae)

developmental and epileptic encephalopathy, 54STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0033363

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 54DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0033363

Submitter: G2P

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 54AR

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: 23708187; 23934111; 25356899; 27652284Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HNRNPU variants in ClinVar

21 Conditions Cataloged
Developmental and epileptic encephalopathy, 54Total: 960
not providedTotal: 225
Inborn genetic diseasesTotal: 139
not specifiedTotal: 74
HNRNPU-related disorderTotal: 31
HNRNPU-related disordersTotal: 10
heterogeneous nuclear ribonucleoprotein G, humanTotal: 8
Intellectual disabilityTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_031844.3. 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.

EffectPLPVUSLBBSum
synonymous
6
clinvar
271
clinvar
1
clinvar
 278
missense
3
clinvar
8
clinvar
334
clinvar
117
clinvar
22
clinvar
 484
nonsense
25
clinvar
13
clinvar
2
clinvar
1
clinvar
 41
start loss
1
clinvar
 1
frameshift
71
clinvar
32
clinvar
6
clinvar
 109
splice donor/acceptor (+/-2bp)
6
clinvar
8
clinvar
9
clinvar
1
clinvar
 24
Total1066135739023937

Highest pathogenic variant AF is 0.00002448217

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_031844.3RefSeqNP_114032.214MANE Select
ENST00000640218.2EnsemblENSP00000491215.114MANE Select
NM_004501.3RefSeqNP_004492.214Standard
ENST00000283179.14EnsemblENSP00000283179.1012Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Spliceosome - Homo sapiens (human)
  • mRNA Processing
  • Metabolism of RNA
  • mRNA Splicing - Major Pathway
  • mRNA Splicing

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • regulation of alternative mRNA splicing, via spliceosome
  • mRNA splicing, via spliceosome
  • osteoblast differentiation
  • chromatin organization

Molecular Function

  • RNA polymerase II proximal promoter sequence-specific DNA binding
  • RNA polymerase II complex binding
  • TFIIH-class transcription factor complex binding
  • DNA binding
  • chromatin binding

Cellular Component

  • nuclear chromosome
  • kinetochore
  • condensed chromosome kinetochore
  • spindle pole
  • nucleus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000283179
Coding exons
14
Length
13377
Individuals with no LoFs
125744
Homozygous LoFs
0
Heterozygous LoFs
4
Defined
125748
p
0.0000159
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.372534560.5550.00002255414
Missense (PolyPhen)1239.760.30181400
Synonymous-2.832141671.280.000008321527
Loss of Function5.84141.70.02400.00000219504

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish0.000200.00020rare
East Asian0.0000550.000054rare
Finnish00.0absent
European (Non-Finnish)0.00000880.0000088rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: DNA- and RNA-binding protein involved in several cellular processes such as nuclear chromatin organization, telomere-length regulation, transcription, mRNA alternative splicing and stability, Xist-mediated transcriptional silencing and mitotic cell progression (PubMed:10490622, PubMed:18082603, PubMed:19029303, PubMed:22325991, PubMed:25986610, PubMed:28622508). Plays a role in the regulation of interphase large-scale gene-rich chromatin organization through chromatin- associated RNAs (caRNAs) in a transcription-dependent manner, and thereby maintains genomic stability (PubMed:1324173, PubMed:8174554, PubMed:28622508). Required for the localization of the long non-coding Xist RNA on the inactive chromosome X (Xi) and the subsequent initiation and maintenance of X-linked transcriptional gene silencing during X-inactivation (By similarity). Plays a role as a RNA polymerase II (Pol II) holoenzyme transcription regulator (PubMed:8174554, PubMed:9353307, PubMed:10490622, PubMed:15711563, PubMed:19617346, PubMed:23811339). Promotes transcription initiation by direct association with the core-TFIIH basal transcription factor complex for the assembly of a functional pre-initiation complex with Pol II in a actin-dependent manner (PubMed:10490622, PubMed:15711563). Blocks Pol II transcription elongation activity by inhibiting the C-terminal domain (CTD) phosphorylation of Pol II and dissociates from Pol II pre-initiation complex prior to productive transcription elongation (PubMed:10490622). Positively regulates CBX5-induced transcriptional gene silencing and retention of CBX5 in the nucleus (PubMed:19617346). Negatively regulates glucocorticoid-mediated transcriptional activation (PubMed:9353307). Key regulator of transcription initiation and elongation in embryonic stem cells upon leukemia inhibitory factor (LIF) signaling (By similarity). Involved in the long non-coding RNA H19-mediated Pol II transcriptional repression (PubMed:23811339). Participates in the circadian regulation of the core clock component ARNTL/BMAL1 transcription (By similarity). Plays a role in the regulation of telomere length (PubMed:18082603). Plays a role as a global pre-mRNA alternative splicing modulator by regulating U2 small nuclear ribonucleoprotein (snRNP) biogenesis (PubMed:22325991). Plays a role in mRNA stability (PubMed:17174306, PubMed:17289661, PubMed:19029303). Component of the CRD-mediated complex that promotes MYC mRNA stabilization (PubMed:19029303). Enhances the expression of specific genes, such as tumor necrosis factor TNFA, by regulating mRNA stability, possibly through binding to the 3'- untranslated region (UTR) (PubMed:17174306). Plays a role in mitotic cell cycle regulation (PubMed:21242313, PubMed:25986610). Involved in the formation of stable mitotic spindle microtubules (MTs) attachment to kinetochore, spindle organization and chromosome congression (PubMed:21242313). Phosphorylation at Ser- 59 by PLK1 is required for chromosome alignement and segregation and progression through mitosis (PubMed:25986610). Contributes also to the targeting of AURKA to mitotic spindle MTs (PubMed:21242313). Binds to double- and single-stranded DNA and RNA, poly(A), poly(C) and poly(G) oligoribonucleotides (PubMed:1628625, PubMed:8068679, PubMed:8174554, PubMed:9204873, PubMed:9405365). Binds to chromatin-associated RNAs (caRNAs) (PubMed:28622508). Associates with chromatin to scaffold/matrix attachment region (S/MAR) elements in a chromatin-associated RNAs (caRNAs)-dependent manner (PubMed:7509195, PubMed:1324173, PubMed:9204873, PubMed:9405365, PubMed:10671544, PubMed:11003645, PubMed:11909954, PubMed:28622508). Binds to the Xist RNA (PubMed:26244333). Binds the long non-coding H19 RNA (PubMed:23811339). Binds to SMN1/2 pre-mRNAs at G/U-rich regions (PubMed:22325991). Binds to small nuclear RNAs (snRNAs) (PubMed:22325991). Binds to the 3'-UTR of TNFA mRNA (PubMed:17174306). Binds (via RNA-binding RGG-box region) to the long non-coding Xist RNA; this binding is direct and bridges the Xist RNA and the inactive chromosome X (Xi) (By similarity). Also negatively regulates embryonic stem cell differentiation upon LIF signaling (By similarity). Required for embryonic development (By similarity). Binds to brown fat long non-coding RNA 1 (Blnc1); facilitates the recruitment of Blnc1 by ZBTB7B required to drive brown and beige fat development and thermogenesis (By similarity). {ECO:0000250|UniProtKB:Q8VEK3, ECO:0000269|PubMed:10490622, ECO:0000269|PubMed:10671544, ECO:0000269|PubMed:11003645, ECO:0000269|PubMed:11909954, ECO:0000269|PubMed:1324173, ECO:0000269|PubMed:15711563, ECO:0000269|PubMed:1628625, ECO:0000269|PubMed:17174306, ECO:0000269|PubMed:17289661, ECO:0000269|PubMed:18082603, ECO:0000269|PubMed:19029303, ECO:0000269|PubMed:19617346, ECO:0000269|PubMed:21242313, ECO:0000269|PubMed:22325991, ECO:0000269|PubMed:23811339, ECO:0000269|PubMed:25986610, ECO:0000269|PubMed:26244333, ECO:0000269|PubMed:28622508, ECO:0000269|PubMed:7509195, ECO:0000269|PubMed:8068679, ECO:0000269|PubMed:8174554, ECO:0000269|PubMed:9204873, ECO:0000269|PubMed:9353307, ECO:0000269|PubMed:9405365}.;
Disease
DISEASE: Epileptic encephalopathy, early infantile, 54 (EIEE54) [MIM:617391]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. {ECO:0000269|PubMed:23708187, ECO:0000269|PubMed:25356899}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.388

Intolerance Scores

LoFtool
0.192
RVIS EVS
-0.6
RVIS percentile EVS
17.75

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.541

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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