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PLA2G6
phospholipase A2 group VI
The PLA2G6 gene provides instructions for an enzyme crucial in fat metabolism and maintaining cell membrane health, and is associated with a spectrum of neurodegenerative disorders. The PLA2G6 gene encodes phospholipase A2 group VI, an enzyme that plays a key role in breaking down phospholipids, which are essential fats.
PLA2G6 is located on the long (q) arm of chromosome 22, at band 22q13.1. Arm ratio per GRCh38 - banding schematic.
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Overview
The PLA2G6 gene, also known as phospholipase A2 group VI, is instrumental in the body's metabolic processes, specifically the breakdown of phospholipids. These fats are fundamental components of cell membranes and are critical for their structural integrity and function.
Disruptions to the PLA2G6 gene's function can lead to impaired phospholipid metabolism, which has significant neurological consequences. This gene is associated with a range of neurodegenerative disorders, often collectively referred to as PLA2G6-associated neurodegeneration (PLAN).
What the gene does
The PLA2G6 gene directs the synthesis of an A2 phospholipase enzyme. This enzyme is primarily involved in the metabolism of phospholipids, a class of fats that form the double layer of cell membranes. Phospholipid metabolism is a crucial process, as it helps to maintain the integrity and fluidity of cellular membranes throughout the body.
Specifically, the PLA2G6 enzyme helps regulate the levels of phosphatidylcholine, a phospholipid that is abundant in cell membranes. Proper functioning of this enzyme is essential for preventing the accumulation of certain lipids that could compromise cell health. When the PLA2G6 enzyme's function is compromised, it can disrupt cell membrane maintenance, particularly in neuronal cells, contributing to neurodegeneration.
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Chromosome location
The PLA2G6 gene is situated on chromosome 22, specifically at position 22q13.1. This location refers to the long (q) arm of chromosome 22, in region 13.1.
Protein structure
The PLA2G6 protein consists of 806 amino acids and features several distinct domains and motifs crucial for its function. It contains multiple ANK (Ankyrin) repeats, including ANK 1 (Repeat) at amino acids 120-147 and 151-181, ANK 2 (Repeat) at 185-215, ANK 3 (Repeat) at 219-248, ANK 4 (Repeat) at 251-281, ANK 5 (Repeat) at 286-312, ANK 6 (Repeat) at 316-345, ANK 7 (Repeat) at 349-378, and ANK 9 (Repeat) at 382-403. A significant PNPLA (Domain) is located between amino acids 481-665. Within this domain are the GXGXXG (Motif) at 485-490, GXSXG (Motif) at 517-521, and DGA/G (Motif) at 652-654. Additionally, the protein includes a Calmodulin-binding (1-9-14 motif) (Region) from amino acids 677-686 and a Calmodulin-binding (IQ motif) (Region) from 748-759.
Key variants
Variants in the PLA2G6 gene can lead to altered or impaired enzyme function, affecting phospholipid metabolism and cell membrane maintenance. Over 50 different pathogenic variants have been identified, particularly in individuals with infantile neuroaxonal dystrophy. These genetic changes can eliminate or severely reduce the activity of the PLA2 group VI enzyme, contributing to a range of neurological symptoms.
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.1117G>C | p.Gly373Arg | Pathogenic | ★★☆☆ | Neurodegeneration with brain iron accumulation |
c.1186+1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Infantile neuroaxonal dystrophy |
c.1213_1214del | p.Leu405fs | Pathogenic/Likely pathogenic | ★★☆☆ | Infantile neuroaxonal dystrophy |
c.1670C>T | p.Ser557Leu | Pathogenic/Likely pathogenic | ★★☆☆ | PLA2G6-associated neurodegeneration |
c.1743-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Infantile neuroaxonal dystrophy |
c.1765_1768del | p.Ser589fs | Pathogenic/Likely pathogenic | ★★☆☆ | Infantile neuroaxonal dystrophy |
c.196_197del | p.Gln66fs | Pathogenic/Likely pathogenic | ★★☆☆ | Infantile neuroaxonal dystrophy |
c.1982C>T | p.Thr661Met | Pathogenic | ★★☆☆ | Autosomal recessive Parkinson disease 14 |
c.1A>G | p.Met1Val | Pathogenic/Likely pathogenic | ★★☆☆ | Infantile neuroaxonal dystrophy |
c.857del | p.Tyr286fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive Parkinson disease 14 |
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
Pathogenic variants in the PLA2G6 gene are associated with a spectrum of neurodegenerative conditions, collectively known as PLA2G6-associated neurodegeneration (PLAN). These include Neurodegeneration with brain iron accumulation 2 (PLA2G6), which can present with varied onset and severity. Other related conditions caused by PLA2G6 variants include infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, and PLA2G6-related dystonia-parkinsonism.
UK clinical status
The PLA2G6 gene is evaluated across several UK NHS national genomic test directories, indicating its clinical relevance in the UK. It holds a 'green' status for a wide array of conditions, including Ataxia and cerebellar anomalies - childhood onset, Dystonia, chorea or related movement disorder (both adult and childhood onset), Early onset dystonia, Hereditary ataxia (adult onset), Hereditary neuropathy or pain disorder, Intellectual disability, Likely inborn error of metabolism, Mitochondrial disorders, Neurodegenerative disorders - adult onset, Parkinson Disease and Complex Parkinsonism, Structural basal ganglia disorders, and Undiagnosed metabolic disorders. This widespread 'green' status signifies that testing for PLA2G6 variants is considered clinically appropriate and beneficial for diagnosing these conditions within the NHS Genomic Medicine Service.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary role of the PLA2G6 gene?
The PLA2G6 gene provides instructions for creating an A2 phospholipase enzyme. This enzyme is crucial for breaking down phospholipids, which are essential fats that maintain the integrity and function of cell membranes.
What conditions are associated with variants in the PLA2G6 gene?
Pathogenic variants in the PLA2G6 gene are linked to a group of conditions known as PLA2G6-associated neurodegeneration (PLAN). This includes Neurodegeneration with brain iron accumulation 2 (PLA2G6), infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, and PLA2G6-related dystonia-parkinsonism.
Why is cell membrane integrity important for neurological health?
Cell membrane integrity is vital for neurological health because neuronal cell membranes facilitate signal transmission and protect the cell's internal environment. Disrupted phospholipid metabolism, due to impaired PLA2G6 function, can compromise these membranes, leading to neurodegeneration.
References
- Schneider SA, Hardy J, Bhatia KP. Syndromes of neurodegeneration with brain iron accumulation (NBIA): an update on clinical presentations, histological and genetic underpinnings, and treatment considerations. Movement disorders : official journal of the Movement Disorder Society. 2012. PMID: 22031173
- McNeill A, Chinnery PF. Neurodegeneration with brain iron accumulation. Handbook of clinical neurology. 2011. PMID: 21496576
- Schneider SA, Bhatia KP. Rare causes of dystonia parkinsonism. Current neurology and neuroscience reports. 2010. PMID: 20694531
- Polster B, Crosier M, Lindsay S. Expression of PLA2G6 in human fetal development: Implications for infantile neuroaxonal dystrophy. Brain research bulletin. 2010. PMID: 20813170
- Engel LA, Jing Z, O'Brien DE. Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia-parkinsonism. PloS one. 2010. PMID: 20886109
- Wu Y, Jiang Y, Gao Z. Clinical study and PLA2G6 mutation screening analysis in Chinese patients with infantile neuroaxonal dystrophy. European journal of neurology. 2009. PMID: 19138334
- Kurian MA, Morgan NV, MacPherson L. Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). Neurology. 2008. PMID: 18443314
- Morgan NV, Westaway SK, Morton JE. PLA2G6, encoding a phospholipase A2, is mutated in neurodegenerative disorders with high brain iron. Nature genetics. 2006. PMID: 16783378
- Khateeb S, Flusser H, Ofir R. PLA2G6 mutation underlies infantile neuroaxonal dystrophy. American journal of human genetics. 2006. PMID: 17033970
- Hayflick SJ. Neurodegeneration with brain iron accumulation: from genes to pathogenesis. Seminars in pediatric neurology. 2006. PMID: 17101457