On this page
PLEKHG5
pleckstrin homology and RhoGEF domain containing G5
The PLEKHG5 gene provides instructions for making a protein involved in cellular processes, with variants linked to certain neurological conditions. The PLEKHG5 gene, full name pleckstrin homology and RhoGEF domain containing G5, codes for a protein essential for various cellular signalling pathways.
PLEKHG5 is located on the short (p) arm of chromosome 1, at band 1p36.31. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 1 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The PLEKHG5 gene encodes a protein that plays a role in cellular communication and maintaining cellular structure. This protein is a guanine nucleotide exchange factor (GEF), specifically acting on a family of small proteins called Rho GTPases. These Rho GTPases are crucial regulators of cell shape, migration, and division, suggesting a broad influence of PLEKHG5 on fundamental cellular functions.
Understanding the PLEKHG5 gene and its protein product helps in deciphering the molecular mechanisms underlying certain inherited neurological conditions. Variants within PLEKHG5 are of clinical interest due to their association with conditions that affect the nervous system.
What the gene does
The PLEKHG5 protein functions as a guanine nucleotide exchange factor (GEF) for Rho GTPases. GEFs activate GTPase proteins by promoting the exchange of GDP (guanosine diphosphate) for GTP (guanosine triphosphate). This activation is a key step in many intracellular signalling cascades that control various cellular activities.
Specifically, the PLEKHG5 protein influences processes such as cell motility, cell adhesion, cytoskeleton reorganisation, and gene expression through its regulation of Rho GTPases. Its involvement in these pathways highlights its importance in the proper development and maintenance of cellular architecture and function, particularly within the nervous system. Dysregulation of these pathways due to genetic variants in PLEKHG5 can therefore contribute to neurological dysfunction.
Video: Genetics 101
Chromosome location
The PLEKHG5 gene is located on the short (p) arm of chromosome 1, specifically at band 1p36.31. This region is towards the end of chromosome 1. The gene occupies approximately 117,143 base pairs of DNA.
Protein structure
The PLEKHG5 protein is composed of 1006 amino acids and features several distinct domains critical for its function. Key structured domains include a DH (Dbl homology) domain from amino acids 336-528, which is characteristic of RhoGEF proteins and mediates the exchange activity. A PH (Pleckstrin Homology) domain is also present from amino acids 584-684, typically involved in binding to phospholipids and membrane localisation. Additionally, the protein contains several disordered regions: amino acids 1-71, 148-198, 212-242, 690-754, 768-820, 837-863, and 950-979, which may contribute to protein-protein interactions and regulatory functions.
Key variants
Variants in the PLEKHG5 gene can include changes to the DNA sequence that may alter the structure or function of the encoded protein. These genetic changes can range from single nucleotide alterations to larger deletions or insertions within the gene. Pathogenic variants are primarily associated with conditions inherited in an autosomal recessive manner, meaning an individual must inherit two copies of the altered gene (one from each parent) to be affected.
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.1132-2A>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease recessive intermediate C |
c.1289C>A | p.Ser430Ter | Pathogenic/Likely pathogenic | ★★☆☆ | PLEKHG5-related disorder |
c.1327G>T | p.Glu443Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronopathy, distal hereditary motor, autosomal recessive 4 |
c.1738G>T | p.Glu580Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease recessive intermediate C |
c.2053C>T | p.Gln685Ter | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.2149G>T | p.Glu717Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease recessive intermediate C |
c.2269G>T | p.Glu757Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Neuronopathy, distal hereditary motor, autosomal recessive 4 |
c.2366_2367del | p.Leu789fs | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease recessive intermediate C |
c.2542C>T | p.Arg848Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Charcot-Marie-Tooth disease recessive intermediate C |
c.2788C>T | p.Arg930Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
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 PLEKHG5 gene are associated with inherited conditions that primarily affect the nervous system. These conditions often fall under the umbrella of hereditary neuropathies, which are disorders affecting the peripheral nerves. Individuals with affected PLEKHG5 genes may experience a range of neurological symptoms depending on the specific variant and its effect on protein function.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic PLEKHG5 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The PLEKHG5 gene is included in several NHS Genomic Medicine Service (GMS) panels within the UK. It is categorised as 'green' for both "Hereditary neuropathy" and "Hereditary neuropathy or pain disorder (R78)" panels, indicating that there is strong evidence for a gene-disease association and that testing for this gene is considered clinically appropriate within these contexts.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the PLEKHG5 gene do?
The PLEKHG5 gene provides instructions for making a protein that acts as a guanine nucleotide exchange factor (GEF). This protein activates other small proteins called Rho GTPases, which are important regulators of various cellular functions like cell shape, movement, and division.
What conditions are associated with PLEKHG5 gene variants?
Variants in the PLEKHG5 gene are associated with certain inherited neurological conditions, primarily hereditary neuropathies. These conditions affect the peripheral nerves and can lead to a range of symptoms impacting nerve function.
How is a condition related to PLEKHG5 inherited?
Conditions associated with the PLEKHG5 gene are typically inherited in an autosomal recessive pattern. This means an individual must inherit two altered copies of the gene, one from each parent, to develop the condition. People with only one altered copy are usually carriers and do not show symptoms.