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HNRNPK
heterogeneous nuclear ribonucleoprotein K
The HNRNPK gene provides instructions for making the heterogeneous nuclear ribonucleoprotein K (hnRNP K), a protein essential for regulating gene activity and protein production. The HNRNPK gene encodes hnRNP K, a protein that plays a crucial role in many cellular functions, including cell growth, differentiation, and programmed cell death.
HNRNPK is located on the long (q) arm of chromosome 9, at band 9q21.32. Arm ratio per GRCh38 - banding schematic.
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Overview
The HNRNPK gene, located on chromosome 9, is responsible for producing heterogeneous nuclear ribonucleoprotein K (hnRNP K) [PMID:24623376]. This protein is highly versatile, capable of binding to both DNA and RNA, as well as interacting with other proteins within the cell. Through these interactions, hnRNP K acts as a central organiser, facilitating communication between various molecular components. It helps to relay signals and manage a range of cellular functions, fundamentally influencing how genetic information is expressed and how proteins are synthesised.
By regulating gene activity and protein levels, hnRNP K contributes to a broad spectrum of cellular processes. These include cellular proliferation (cell growth and division), differentiation (the specialisation of cells into distinct types), and apoptosis (the controlled elimination of cells when they are no longer required).
In the brain, for example, the hnRNP K protein may be instrumental in synaptic plasticity-the ability of the connections between nerve cells (synapses) to adapt and change over time in response to stimuli. This process is vital for essential cognitive functions such as learning and memory. Furthermore, it contributes to the growth of nerve cell extensions, known as axons, which are indispensable for the efficient transmission of nerve impulses. While its importance in other systems and processes is recognised, the specific mechanisms are still under active investigation.
What the gene does
The heterogeneous nuclear ribonucleoprotein K (hnRNP K) protein, encoded by the HNRNPK gene, serves as a critical regulator of gene expression and cellular function. Its primary mechanism involves binding to nucleic acids, specifically DNA and RNA, and other proteins to act as a molecular scaffold. This scaffolding function allows it to bring diverse molecules together, creating essential hubs for signal transduction and the precise control of cellular activities [PMID:24623376].
By influencing how genes are transcribed into RNA and how RNA is translated into proteins, hnRNP K participates in a wide array of biological processes. These include the regulation of cell growth and division (proliferation), the specialisation of cells into different types (differentiation), and programmed cell death (apoptosis), which is vital for tissue homeostasis and removing damaged cells. The protein's ability to selectively bind to specific sequences in nucleic acids enables it to fine-tune gene expression in response to cellular needs and external cues. In the nervous system, hnRNP K plays particular roles. It is thought to be involved in synaptic plasticity, the dynamic process by which neuronal connections strengthen or weaken over time, underpinning learning and memory formation [PMID:24623376]. Additionally, hnRNP K assists in the growth and maintenance of axons, the long extensions of nerve cells that transmit electrical signals throughout the body. The diverse functions of hnRNP K underscore its fundamental importance across multiple biological systems, although many of its specific roles are still being thoroughly explored.
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Chromosome location
The HNRNPK gene is situated on chromosome 9, specifically at band 9q21.32. This location refers to the long (q) arm of chromosome 9, within region 2, band 1, and sub-band 32. Humans typically have two copies of chromosome 9, one inherited from each parent, and thus two copies of the HNRNPK gene. The gene itself consists of multiple exons, which are the coding segments that are ultimately translated into the hnRNP K protein after introns (non-coding segments) are removed during RNA processing.
Protein structure
The heterogeneous nuclear ribonucleoprotein K (hnRNP K) protein is composed of 463 amino acids and exhibits a complex domain architecture crucial for its varied functions. An N-terminal disordered region is located between amino acids 1-37. Within this N-terminal segment, a notable region from amino acids 1-276 is essential for interaction with DDX1, and another, spanning 35-197, is involved in interaction with ASFV p30. The protein contains multiple K-homology (KH) domains, which are crucial for RNA binding. The first of these, KH 1, is located at amino acids 42-104, while KH 2 is found between amino acids 144-209.
Further structural characteristics include a 1-1 Repeat at amino acids 54-76 and a 3-1 Repeat at 59-62. Several repetitive sequence motifs are also present, including 2 X 22 AA approximate repeats covering amino acids 54-421, and 5 X 4 AA repeats of G-X-G-G ranging from amino acids 59-407. A significant RNA-binding RGG-box motif is situated between amino acids 236-273. Additionally, a region from amino acids 209-337 mediates interaction with ZIK1. Another disordered region is found between amino acids 250-329, which also contains a 2-1 Repeat (amino acids 245-250) and a 3-2 Repeat (amino acids 257-260) along with 2 X 6 AA approximate repeats from amino acids 245-329. These various domains and motifs enable hnRNP K to interact with different nucleic acids and proteins, underpinning its regulatory roles.
Key variants
Genetic variations within the HNRNPK gene can lead to alterations in the structure or function of the hnRNP K protein. These variants include point mutations, small insertions or deletions, and larger chromosomal rearrangements that may affect the gene's expression or the protein's coding sequence. Pathogenic variants can disrupt the protein's ability to bind to DNA, RNA, or other interacting proteins, thereby impairing its crucial roles in gene regulation, cell proliferation, and differentiation.
Over 20 distinct variants in the HNRNPK gene have been identified as causative for specific inherited conditions. The clinical consequences of these variants can depend on their precise location within the gene and their impact on protein function. Some variants may lead to a complete loss of protein function, while others might result in proteins with altered or reduced activity. The diverse nature of these genetic changes contributes to the variable clinical presentations observed in affected individuals.
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.1008+1G>A | - | Pathogenic | ★★☆☆ | Au-Kline syndrome |
c.1108+1G>T | - | Pathogenic | ★★☆☆ | Au-Kline syndrome |
c.136C>T | p.Arg46Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Au-Kline syndrome |
c.257G>A | p.Arg86His | Pathogenic/Likely pathogenic | ★★☆☆ | Au-Kline syndrome |
c.673T>C | p.Tyr225His | Pathogenic/Likely pathogenic | ★★☆☆ | Au-Kline syndrome |
c.779dup | p.Phe261_Asp262insTer | Pathogenic | ★★☆☆ | Au-Kline syndrome |
c.859C>T | p.Arg287Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.886C>T | p.Arg296Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Au-Kline syndrome |
c.998dup | p.Tyr333Ter | Pathogenic | ★★☆☆ | Au-Kline syndrome |
c.1074dup | p.Met359fs | Pathogenic | ★☆☆☆ | Au-Kline 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
Genetic changes in the HNRNPK gene are linked to several human health conditions, most notably Au-Kline syndrome. Over 20 different genetic alterations in the HNRNPK gene have been identified as causes of this syndrome [PMID:24623376]. Symptoms typically include weak muscle tone (hypotonia), impaired cognitive development, delays in speech and walking, and distinctive facial features. Other body systems, such as the heart and kidneys, can also be affected. Additionally, abnormal hnRNP K function has been implicated in certain cancers, particularly acute myeloid leukaemia (AML), where deletions affecting the gene on chromosome 9 are sometimes observed. These conditions highlight the critical role of HNRNPK in normal development and cellular regulation.
No disease links recorded for this gene in our reference set.
UK clinical status
The HNRNPK gene is recognised within the UK's National Health Service (NHS) clinical genomics programme, as evidenced by its inclusion in several diagnostic panels. It is listed as 'green' in PanelApp for Clefting, DDG2P (a database of genes associated with developmental disorders), Foetal anomalies (specifically under R21), and Intellectual disability (under R29). HNRNPK is also green for Rare syndromic craniosynostosis or isolated multisuture synostosis (R100). The 'green' status indicates that there is sufficient evidence for the gene to be considered clinically actionable within these contexts, indicating a strong association between variants in HNRNPK and these specific conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Maintaining a balanced lifestyle, including a diverse diet and regular physical activity, generally supports overall health and cellular function. These broad health recommendations can indirectly support cellular homeostasis, which is influenced by proteins like hnRNP K. No specific lifestyle interventions are known to directly target HNRNPK gene function, but a healthy lifestyle can foster robust physiological processes generally.
Supplement considerations
Currently, there is no conclusive scientific evidence to suggest that specific dietary supplements can prevent, treat, or directly influence conditions associated with the HNRNPK gene. The hnRNP K protein is involved in fundamental cellular processes, and its function is not known to be modulated by common supplements. Individuals considering any supplements should consult with a healthcare professional to discuss potential benefits, risks, and interactions with other medications or health conditions, as some supplements may have unintended effects.
Frequently asked questions
What is the HNRNPK gene?
The HNRNPK gene provides the genetic instructions for making heterogeneous nuclear ribonucleoprotein K (hnRNP K), a protein that plays a vital role in regulating gene activity and protein production within cells.
What does hnRNP K protein do?
The hnRNP K protein binds to DNA, RNA, and other proteins, acting as a molecular bridge to coordinate various cellular functions. It is involved in cell growth, division, specialisation, and programmed cell death.
What conditions are associated with the HNRNPK gene?
Variants in the HNRNPK gene are associated with Au-Kline syndrome, a developmental disorder, and have also been implicated in certain types of cancer, such as acute myeloid leukaemia (AML).
How does HNRNPK affect brain function?
In the brain, the hnRNP K protein is thought to be involved in synaptic plasticity, which is crucial for learning and memory. It also contributes to the growth of axons, nerve cell extensions essential for nerve impulse transmission.
Is the HNRNPK gene included in NHS genetic testing?
Yes, the HNRNPK gene is included in several NHS genomic medicine diagnostic panels, indicating its clinical relevance for conditions such as foetal anomalies, intellectual disability, and rare syndromic craniosynostosis.
References
- Naarmann-de Vries IS, Sackmann Y, Klein F. Characterization of acute myeloid leukemia with del(9q) - Impact of the genes in the minimally deleted region. Leukemia research. 2019. PMID: 30476680
- Xu Y, Wu W, Han Q. New Insights into the Interplay between Non-Coding RNAs and RNA-Binding Protein HnRNPK in Regulating Cellular Functions. Cells. 2019. PMID: 30658384
- Okamoto N. Okamoto syndrome has features overlapping with Au-Kline syndrome and is caused by HNRNPK mutation. American journal of medical genetics. Part A. 2019. PMID: 30793470
- Au PYB, Goedhart C, Ferguson M. Phenotypic spectrum of Au-Kline syndrome: a report of six new cases and review of the literature. European journal of human genetics : EJHG. 2018. PMID: 29904177
- Gallardo M, Lee HJ, Zhang X. hnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies. Cancer cell. 2015. PMID: 26412324
- Folci A, Mapelli L, Sassone J. Loss of hnRNP K impairs synaptic plasticity in hippocampal neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2014. PMID: 24990929
- Hutchins EJ, Szaro BG. c-Jun N-terminal kinase phosphorylation of heterogeneous nuclear ribonucleoprotein K regulates vertebrate axon outgrowth via a posttranscriptional mechanism. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2013. PMID: 24027268
- Sweetser DA, Peniket AJ, Haaland C. Delineation of the minimal commonly deleted segment and identification of candidate tumor-suppressor genes in del(9q) acute myeloid leukemia. Genes, chromosomes & cancer. 2005. PMID: 16015647
- Bomsztyk K, Denisenko O, Ostrowski J. hnRNP K: one protein multiple processes. BioEssays : news and reviews in molecular, cellular and developmental biology. 2004. PMID: 15170860
- Adam MP, Bick S, Mirzaa GM. Au-Kline Syndrome. 1993. PMID: 30998304