PQBP1

protein-coding

polyglutamine binding protein 1, the group of Spliceosomal B complex

Gene summary

This gene encodes a nuclear polyglutamine-binding protein that is involved with transcription activation. The encoded protein contains a WW domain. Mutations in this gene have been found in patients with Renpenning syndrome 1 and other syndromes with X-linked cognitive disability. Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene.[provided by RefSeq, Nov 2009]

Previous symbols:

RENS1
MRXS8
SHS
MRX55
MRX2
MRXS3

MANE transcript

NM_001032382.2

Inheritance

ClinVar variants

P:39U:114B:43

Top phenotype

Renpenning syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chrX:48,890,197-48,903,402

External References & Databases

Ensembl (ENSG00000102103)

Transcript & Mutation Effects

hg38 • Region Span ~13.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked intellectual disability, Porteous typeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019766

Submitter: Orphanet

Renpenning syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010653

Submitter: PanelApp Australia

hamel cerebro-palato-cardiac syndromeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019767

Submitter: Orphanet

Renpenning syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010653

Submitter: Ambry Genetics

Renpenning syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010653

Submitter: G2P

Renpenning syndromeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010653

Submitter: ClinGen

*PQBP1* is located on chromosome X at Xp11.23 and encodes polyglutamine-binding protein 1, a nuclear protein that regulates pre-mRNA splicing and transcription. In the cytoplasm, PQBP1 can be localized in stress granules and plays a role in translation of mRNAs. *PQBP1* was first reported in relation to X-linked Renpenning syndrome in 2003 (Kalscheuer et al., PMID: 14634649). Renpenning syndrome is characterized by developmental delay, intellectual disability, microcephaly, short stature, lean body build, and dysmorphic facial features. Less common findings include cardiac defects, cleft palate, coloboma, anal anomalies, small testes, muscular atrophy, and autism spectrum disorder or autistic behavior. The full phenotype is only found in males; female carriers are usually unaffected. Nine variants (6 frameshift, 2 nonsense and 1 missense) that have been reported in 13 male probands in 8 publications (PMIDs: 14634649, 15024694, 15782410, 16493439, 16740914, 20950397, 21267006, 30244542) are included in this curation. Variants in this gene segregated with disease in 28 additional male family members and in unaffected female carriers. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The most common variants are frameshift variants affecting a stretch of six AG dinucleotides in exon 5, including two recurrent variants (c.459_462delAGAG and c.461_462dupAG). These variants have variable effects in patient lymphoblastoid cell lines, including partial nonsense-mediated mRNA decay, increased production of PQBP1 transcripts that skip exon 5, the production of a truncated PQBP1 protein, and increased production of a short PQBP1 isoform that is also present in controls (PMID: 19847789). These findings suggest that the clinical phenotype could be caused by loss of wild-type PQBP1 in combination with the presence of a truncated protein that could exert a dominant-negative or gain-of-function effect (PMIDs: 19847789, 28073926). This gene-disease relationship is also supported by a conditional knockout mouse model with microcephaly (PMID: 25070536), aberrant alternative splicing and reduced neurite outgrowth after knockdown of *Pqbp1* in mouse embryonic cortical neurons (PMID: 23512658), and functional studies demonstrating the pathogenicity of patient variants (PMIDs: 24781215, 28073926, 38030819). In summary, there is definitive evidence supporting the relationship between *PQBP1* and X-linked Renpenning syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on November 7, 2018. It was reevaluated on June 30, 2026 (SOP Version 12). As a result of this reevaluation, the classification did not change.

X-linked intellectual disability, Sutherland-Haan typeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019769

Submitter: Orphanet

Renpenning syndromeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010653

Submitter: Labcorp Genetics (formerly Invitae)

X-linked intellectual disability, Golabi-Ito-hall typeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019768

Submitter: Orphanet

Clinical Genomic Database (CGD)

Renpenning syndrome 1XL

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Gastrointestinal; Genitourinary; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 13981686; 3177467; 7943045; 9599645; 11950858; 14634649; 15024694; 15811016; 15782410; 16493439; 16740914; 17033686; 20886605; 20950397; 21204222; 21267006; 21315190; 22710169

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PQBP1 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 142

Renpenning syndromeTotal: 58

Inborn genetic diseasesTotal: 46

not specifiedTotal: 25

PQBP1-related disorderTotal: 15

Intellectual disabilityTotal: 4

See casesTotal: 3

MicrocephalyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001032382.2. 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			9 clinvar	27 clinvar	4 clinvar	40
missense	1 clinvar	7 clinvar	96 clinvar	12 clinvar		116
nonsense	2 clinvar	5 clinvar	1 clinvar			8
start loss						0
frameshift	13 clinvar	8 clinvar	1 clinvar			22
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	7 clinvar			10
Total	17	22	114	39	4	196

Highest pathogenic variant AF is 0.000005463988

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 109 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001032382.2	RefSeq	NP_001027554.1	6	MANE Select
ENST00000447146.7	Ensembl	ENSP00000391759.2	6	MANE Select
NM_001032381.2	RefSeq	NP_001027553.1	6	Standard
NM_001032383.2	RefSeq	NP_001027555.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Spliceosome - Homo sapiens (human)
Metabolism of RNA
mRNA Splicing - Major Pathway
mRNA Splicing
Processing of Capped Intron-Containing Pre-mRNA

Biological Process

alternative mRNA splicing, via spliceosome
mRNA splicing, via spliceosome
activation of innate immune response
positive regulation of defense response to virus by host
regulation of transcription, DNA-templated

Molecular Function

DNA binding
double-stranded DNA binding
transcription coactivator activity
protein binding
ribonucleoprotein complex binding

Cellular Component

nucleus
nucleoplasm
cytosol
cytoplasmic stress granule
nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000218224
Coding exons: 6
Length: 5226
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.92	65	126	0.518	0.0000111	1712
Missense (PolyPhen)		16	50.663	0.31581		664
Synonymous	0.232	48	50.1	0.958	0.00000441	515
Loss of Function	2.56	1	9.51	0.105	7.31e-7	159

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	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Intrinsically disordered protein that acts as a scaffold, and which is involved in different processes, such as pre-mRNA splicing, transcription regulation, innate immunity and neuron development (PubMed:10198427, PubMed:10332029, PubMed:12062018, PubMed:20410308, PubMed:23512658). Interacts with splicing-related factors via the intrinsically disordered region and regulates alternative splicing of target pre-mRNA species (PubMed:10332029, PubMed:12062018, PubMed:23512658, PubMed:20410308). May suppress the ability of POU3F2 to transactivate the DRD1 gene in a POU3F2 dependent manner. Can activate transcription directly or via association with the transcription machinery (PubMed:10198427). May be involved in ATXN1 mutant-induced cell death (PubMed:12062018). The interaction with ATXN1 mutant reduces levels of phosphorylated RNA polymerase II large subunit (PubMed:12062018). Involved in the assembly of cytoplasmic stress granule, possibly by participating to the transport of neuronal RNA granules (PubMed:21933836). Also acts as an innate immune sensor of infection by retroviruses, such as HIV, by detecting the presence of reverse-transcribed DNA in the cytosol (PubMed:26046437). Directly binds retroviral reverse- transcribed DNA in the cytosol and interacts with CGAS, leading to activate the cGAS-STING signaling pathway, triggering type-I interferon production (PubMed:26046437). {ECO:0000269|PubMed:10198427, ECO:0000269|PubMed:10332029, ECO:0000269|PubMed:12062018, ECO:0000269|PubMed:20410308, ECO:0000269|PubMed:21933836, ECO:0000269|PubMed:23512658, ECO:0000269|PubMed:26046437}.;
Disease: DISEASE: Renpenning syndrome 1 (RENS1) [MIM:309500]: A X-linked mental retardation syndrome characterized by mental retardation, microcephaly, short stature, and small testes. The craniofacies tends to be narrow and tall with upslanting palpebral fissures, abnormal nasal configuration, cupped ears, and short philtrum. The nose may appear long or bulbous, with overhanging columella. Less consistent manifestations include ocular colobomas, cardiac malformations, cleft palate, and anal anomalies. {ECO:0000269|PubMed:14634649, ECO:0000269|PubMed:16740914, ECO:0000269|PubMed:20410308, ECO:0000269|PubMed:21315190, ECO:0000269|PubMed:23512658, ECO:0000269|PubMed:26046437}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.158

Intolerance Scores

LoFtool: 0.226
RVIS EVS: -0.03
RVIS percentile EVS: 51.04

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Indispensability pred.: E
Indispensability score: 0.914

Gene Damage Prediction

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