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PLA2G6
phospholipase A2 group VI
The PLA2G6 gene provides instructions for an enzyme crucial in phospholipid metabolism and maintaining cellular membrane integrity, with variants linked to a spectrum of neurodegenerative disorders. The PLA2G6 gene encodes phospholipase A2 group VI, an enzyme vital for breaking down specific fats called phospholipids.
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, provides the genetic blueprint for an enzyme involved in lipid metabolism. This enzyme plays a key role in breaking down phospholipids, which are fundamental components of cell membranes.
Disruptions to the function of the PLA2G6 enzyme due to genetic variants can lead to a spectrum of neurodegenerative disorders, collectively referred to as PLA2G6-associated neurodegeneration (PLAN). These conditions typically affect the nervous system, leading to progressive neurological dysfunction.
What the gene does
The PLA2G6 gene directs the production of an A2 phospholipase enzyme, specifically PLA2 group VI. This enzyme is primarily responsible for the metabolism of phospholipids, a class of fats that form the structural basis of cell membranes. Phospholipid metabolism is a critical process for numerous cellular functions, including the maintenance and repair of cell membranes.
Specifically, the PLA2G6 enzyme contributes to regulating levels of phosphatidylcholine, a phospholipid that is highly abundant in cell membranes. Proper regulation of these lipids is essential for ensuring cell membrane integrity and overall cellular health. When the PLA2G6 enzyme's function is impaired, it can disrupt cell membrane maintenance, contributing to the cellular damage observed in associated conditions.
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Chromosome location
The PLA2G6 gene is located on chromosome 22, specifically at position 22q13.1. This means it resides on the long (q) arm of chromosome 22. The gene spans a significant region of this chromosome, and its precise location influences how it is inherited and expressed.
Protein structure
The PLA2G6 protein is composed of 806 amino acids and features several distinct domains and motifs. 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 functional region is the PNPLA (Domain) located from amino acids 481-665, which contains key motifs such as GXGXXG (Motif) at 485-490, GXSXG (Motif) at 517-521, and DGA/G (Motif) at 652-654. Additionally, the protein has two Calmodulin-binding regions: one with a 1-9-14 motif at 677-686 and another with an IQ motif at 748-759.
Key variants
Genetic variations within the PLA2G6 gene can alter the function or production of the PLA2 group VI enzyme. These variants include changes that can eliminate or severely reduce enzyme activity. The inheritance pattern for conditions associated with PLA2G6 variants can vary.
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 | ★★☆☆ | Infantile neuroaxonal dystrophy |
c.1743-2A>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Infantile neuroaxonal dystrophy |
c.1765_1768del | p.Ser589fs | Pathogenic/Likely pathogenic | ★★☆☆ | PLA2G6-associated neurodegeneration |
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 | ★★☆☆ | PLA2G6-associated neurodegeneration |
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 linked to a spectrum of neurodegenerative disorders, often grouped under the umbrella term PLA2G6-associated neurodegeneration (PLAN). These include infantile neuroaxonal dystrophy, a progressive neurological condition typically presenting in early childhood with intellectual disability and movement problems. Atypical neuroaxonal dystrophy and PLA2G6-related dystonia-parkinsonism are also associated with PLA2G6 variants, generally involving later-onset neurological decline.
- Neurodegeneration with brain iron accumulation 2 (PLA2G6) Dedicated page coming soon
UK clinical status
The PLA2G6 gene is recognised in the UK's NHS Genomic Medicine Service. It is listed as 'green' (meaning there is strong evidence for its gene-disease association) on multiple NHS Genomic Test Directory panels. These include panels for Ataxia and cerebellar anomalies - childhood onset, Dystonia, chorea or related movement disorder (both adult and childhood onset), Hereditary ataxia, Early onset or syndromic epilepsy, Intellectual disability, Mitochondrial disorders, and Parkinson Disease and Complex Parkinsonism, among others.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main role of the PLA2G6 gene?
The PLA2G6 gene provides instructions for making an enzyme called phospholipase A2 group VI. This enzyme is crucial for breaking down phospholipids, which are essential fats that help maintain the integrity of cell membranes throughout the body.
What conditions are associated with changes in the PLA2G6 gene?
Variants in the PLA2G6 gene are associated with a group of neurodegenerative disorders collectively known as PLA2G6-associated neurodegeneration (PLAN). These include infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, and PLA2G6-related dystonia-parkinsonism, all of which involve progressive neurological decline.
How do PLA2G6 gene variants affect cell function?
When the PLA2G6 gene has pathogenic variants, the enzyme it produces may not function correctly or at all. This impairment disrupts the normal metabolism of phospholipids, which can lead to problems with maintaining the structure and function of cell membranes, particularly in the nervous system.
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