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PQBP1
polyglutamine binding protein 1
The PQBP1 gene provides instructions for producing polyglutamine-binding protein 1, a protein thought to be crucial for normal brain development and the processing of genetic information in neurons. PQBP1 encodes the polyglutamine-binding protein 1, which plays a role in the processing and transport of RNA within cells, particularly in neurons.
PQBP1 is located on the short (p) arm of chromosome X, at band Xp11.23. Arm ratio per GRCh38 - banding schematic.
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Overview
The PQBP1 gene is responsible for producing polyglutamine-binding protein 1. This protein is involved in regulating gene expression, especially within nerve cells, and is considered vital for typical brain development.
While its precise mechanisms are still under investigation, the protein's ability to bind to specific protein components suggests a role in intricate cellular processes. Variants within PQBP1 are primarily associated with X-linked intellectual disability syndromes.
What the gene does
The polyglutamine-binding protein 1, encoded by the PQBP1 gene, is known to bind to sequences of multiple glutamine amino acids found in other proteins. This binding activity is thought to be involved in the processing and transportation of RNA, which carries genetic instructions for protein production.
In neurons, this protein is specifically located within RNA granules. These granules facilitate the movement and storage of RNA until it is needed for protein synthesis or degradation. By influencing RNA dynamics, PQBP1 contributes to the regulation of gene expression, a function critical for healthy brain development. Abnormalities in PQBP1 can lead to disruptions in these crucial cellular processes, affecting neuronal function.
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Chromosome location
The PQBP1 gene is located on the X chromosome, specifically at the Xp11.23 position. As an X-linked gene, its inheritance pattern differs between males and females. The protein it encodes consists of 265 amino acids.
Protein structure
The polyglutamine-binding protein 1 features several distinct domains. At amino acids 46-80, it contains a WW domain, which is typically involved in protein-protein interactions. A large disordered region spans amino acids 94-265. Within this region, there are several repeat elements. These include five approximate tandem repeats of 7 amino acids (D-R-[SG]-H-D-K-S) from amino acids 104-138, comprising the 1-1 (amino acids 104-110), 1-2 (amino acids 111-117), 1-3 (amino acids 118-124), 1-4 (amino acids 125-131), and 1-5 (amino acids 132-138) repeats. Further repeats include three tandem repeats of 2 amino acids ([DE]-R) from amino acids 139-144, designated as 2-1 (amino acids 139-140), 2-2 (amino acids 141-142), and 2-3 (amino acids 143-144) repeats. Additionally, there are seven tandem repeats of 2 amino acids ([DE]-R) from amino acids 150-163, with the 3-1 (amino acids 150-151) and 3-2 (amino acids 152-153) repeats explicitly identified.
Key variants
Variants in the PQBP1 gene can lead to changes in the polyglutamine-binding protein 1, potentially affecting its structure and function. Many identified variants result in a shortened or otherwise non-functional protein. Such alterations are typically associated with disrupted RNA processing and neuronal development.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.292+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Renpenning syndrome |
c.450_453del | p.Asp150fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.459_462del | p.Arg153fs | Pathogenic/Likely pathogenic | ★★☆☆ | PQBP1-related disorder |
c.461_462del | p.Glu154fs | Pathogenic | ★★☆☆ | Renpenning syndrome |
c.461_462dup | p.Arg155fs | Pathogenic | ★★☆☆ | Renpenning syndrome |
c.586C>T | p.Arg196Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Renpenning syndrome |
c.623_624del | p.Ser208fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.640dup | p.Arg214fs | Pathogenic | ★★☆☆ | Renpenning syndrome |
c.641_642insC | - | Pathogenic | ★☆☆☆ | Renpenning syndrome |
c.632dup | p.Asp211fs | Pathogenic | ★☆☆☆ | Renpenning syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in the PQBP1 gene are primarily linked to Renpenning syndrome (XLR), an X-linked disorder that almost exclusively affects males. This condition is characterised by intellectual disability and specific physical features. Other associated conditions include Anophthalmia/Microphthalmia and Coloboma, indicating a broader role for PQBP1 in early developmental processes.
- Renpenning syndrome Dedicated page coming soon
UK clinical status
The PQBP1 gene is recognised in the UK by the NHS Genomic Medicine Service through its inclusion on several Gene PanelApp green lists. These include panels for DDG2P, Foetal anomalies (R21), Intellectual disability, and Severe microcephaly (R88), indicating that it is considered a clinically actionable gene for these conditions within the NHS.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the PQBP1 gene?
The PQBP1 gene provides instructions for the polyglutamine-binding protein 1, which plays a critical role in processing and transporting RNA within cells, particularly neurons. This function is essential for regulating gene expression and normal brain development.
Which conditions are associated with PQBP1 gene variants?
Variants in the PQBP1 gene are primarily associated with Renpenning syndrome, an X-linked intellectual disability disorder. It has also been linked to conditions such as Anophthalmia/Microphthalmia and Coloboma.
Why is PQBP1 considered important for brain development?
In nerve cells, PQBP1 is found in RNA granules, which manage the transport and storage of RNA. By controlling how genetic information is used in neurons through these mechanisms, PQBP1 helps to ensure proper brain development.
References
- Germanaud D, Rossi M, Bussy G. The Renpenning syndrome spectrum: new clinical insights supported by 13 new PQBP1-mutated males. Clinical genetics. 2011. PMID: 20950397
- Flynn M, Zou YS, Milunsky A. Whole gene duplication of the PQBP1 gene in syndrome resembling Renpenning. American journal of medical genetics. Part A. 2011. PMID: 21204222
- Kunde SA, Musante L, Grimme A. The X-chromosome-linked intellectual disability protein PQBP1 is a component of neuronal RNA granules and regulates the appearance of stress granules. Human molecular genetics. 2011. PMID: 21933836
- Musante L, Kunde SA, Sulistio TO. Common pathological mutations in PQBP1 induce nonsense-mediated mRNA decay and enhance exclusion of the mutant exon. Human mutation. 2010. PMID: 19847789
- Tapia VE, Nicolaescu E, McDonald CB. Y65C missense mutation in the WW domain of the Golabi-Ito-Hall syndrome protein PQBP1 affects its binding activity and deregulates pre-mRNA splicing. The Journal of biological chemistry. 2010. PMID: 20410308
- Takahashi M, Mizuguchi M, Shinoda H. Polyglutamine tract binding protein-1 is an intrinsically unstructured protein. Biochimica et biophysica acta. 2009. PMID: 19303059
- Martínez-Garay I, Tomás M, Oltra S. A two base pair deletion in the PQBP1 gene is associated with microphthalmia, microcephaly, and mental retardation. European journal of human genetics : EJHG. 2007. PMID: 17033686
- Cossée M, Demeer B, Blanchet P. Exonic microdeletions in the X-linked PQBP1 gene in mentally retarded patients: a pathogenic mutation and in-frame deletions of uncertain effect. European journal of human genetics : EJHG. 2006. PMID: 16493439
- Lubs H, Abidi FE, Echeverri R. Golabi-Ito-Hall syndrome results from a missense mutation in the WW domain of the PQBP1 gene. Journal of medical genetics. 2006. PMID: 16740914
- Stevenson RE, Bennett CW, Abidi F. Renpenning syndrome comes into focus. American journal of medical genetics. Part A. 2005. PMID: 15782410
- Lenski C, Abidi F, Meindl A. Novel truncating mutations in the polyglutamine tract binding protein 1 gene (PQBP1) cause Renpenning syndrome and X-linked mental retardation in another family with microcephaly. American journal of human genetics. 2004. PMID: 15024694
- Kleefstra T, Franken CE, Arens YH. Genotype-phenotype studies in three families with mutations in the polyglutamine-binding protein 1 gene (PQBP1). Clinical genetics. 2004. PMID: 15355434
- Okazawa H, Sudol M, Rich T. PQBP-1 (Np/PQ): a polyglutamine tract-binding and nuclear inclusion-forming protein. Brain research bulletin. 2001. PMID: 11719261