Alternative titles; symbols
HGNC Approved Gene Symbol: PLA2G6
SNOMEDCT: 52713000;
Cytogenetic location: 22q13.1 Genomic coordinates (GRCh38) : 22:38,111,495-38,181,830 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q13.1 | Infantile neuroaxonal dystrophy 1 | 256600 | Autosomal recessive | 3 |
| Neurodegeneration with brain iron accumulation 2B | 610217 | Autosomal recessive | 3 | |
| Parkinson disease 14, autosomal recessive | 612953 | Autosomal recessive | 3 |
Phospholipases A2 (PLA2s) catalyze hydrolysis of the sn-2 acyl-ester bonds in phospholipids, leading to the release of arachidonic acid and other fatty acids. PLA2G6 is a calcium-independent PLA2 (Larsson Forsell et al., 1999).
Tang et al. (1997) purified an 85-kD cytosolic calcium-independent PLA2, termed iPLA2, from Chinese hamster ovary (CHO) cells. They isolated a partial human cDNA from a Burkitt lymphoma cDNA library by screening with a CHO cDNA. Northern blot analysis revealed that iPLA2 is expressed in a variety of rodent tissues.
Larsson et al. (1998) cloned human iPLA2 cDNAs and discovered multiple mRNA isoforms resulting from alternative splicing. The full-length cDNA encodes an 806-amino acid protein with a lipase motif and 8 ankyrin repeats. Human and rodent iPLA2 share 90% overall amino acid sequence identity, with the human sequence differing in containing a 54-residue insertion that would interrupt the last putative ankyrin repeat. Two of the alternatively spliced forms encode only the ankyrin repeat region of the protein. Coexpression of these variants with the active iPLA2 enzyme resulted in a decrease of the enzyme's activity.
By computational analysis, Larsson Forsell et al. (1999) identified several human iPLA2 variants that were alternatively spliced at exons 3, 9, 9a, and 10a, as well as part of exon 14. Northern blot analysis detected iPLA2 transcripts of 1.8, 2.0, 3.2, and 4.2 kb. The 2.0-kb variant was expressed at variable levels in all tissues examined, the 3.2-kb and 4.2-kb transcripts were expressed at variable levels in most tissues examined, and the 1.8-kb transcript was expressed predominantly in heart and skeletal muscle, with lower levels in bone marrow. Western blot analysis of fractionated transfected COS-7 cells showed that full-length human iPLA2 associated with membranes. Hydropathy plot and bioinformatic analyses suggested that iPLA2 contains 2 hydrophobic regions that may be transmembrane domains.
Using rat iPla2 to screen a human insulinoma cDNA library, followed by RT-PCR of human islet RNA, Ma et al. (1999) cloned long and short iPLA2 splice variants. The short variant lacks an insert encoding a 54-amino acid proline-rich region in the long variant. This insert interrupts the last putative ankyrin repeat and is likely to function as a linker region that separates the N-terminal protein-binding domain from the C-terminal catalytic domain. RT-PCR detected these 2 transcripts in a human promonocytic cell line and in normal islet cells. SDS-PAGE showed that the recombinant short and long isoforms of human iPLA2 had apparent molecular masses of 85 kD and 88 kD, respectively.
Larsson Forsell et al. (1999) determined that the PLA2G6 gene contains 19 exons, including the alternative exons 9a and 10a, and spans more than 69 kb. The promoter region lacks a TATA box, but contains a CpG island and several potential SP1 (189906)-binding sites. The 5-prime flanking region also contains an inverted MER53 sequence and an Alu element.
Ma et al. (1999) mapped the PLA2G6 gene to chromosome 22q13.1 by FISH.
Tang et al. (1997) found that expression of the hamster iPla2 cDNA generated an active 85-kD protein that selectively hydrolyzed sn-2 over sn-1 fatty acids.
Larsson Forsell et al. (1999) found that COS-7 cells expressing full-length human iPLA2 and rat vascular smooth muscle cells showed Ca(2+)-independent release of arachidonic acid from radiolabeled phospholipids, and that the activity was associated with the membrane fractions.
Ma et al. (1999) found that both recombinant short and long isoforms of human iPLA2 had Ca(2+)-independent PLA2 activity in cytosolic and membrane fractions. Their activities were inhibited by bromoenol lactone, an iPLA2 suicide substrate. The long iPLA2 isoform, but not the short isoform, was activated by ATP.
Turk and Ramanadham (2004) stated that the shorter iPLA2 isoforms that lack the C-terminal catalytic domain function as negative modulators of iPLA2-beta, the full-length isoform. They also noted that iPLA2-beta can be proteolytically processed to yield truncated products that are constitutively active. Turk and Ramanadham (2004) reviewed the role of iPLA2 in phospholipid remodeling, signal transduction, cell proliferation, and endoplasmic reticulum stress-mediated apoptosis. They stated that, in pancreatic islets, beta cells, and insulinoma cells, iPLA2-beta participates in glucose-stimulated insulin secretion, but it is not involved in membrane phospholipid remodeling.
Arachidonic acid and its metabolites are involved in regulation of endothelial cell proliferation. Herbert and Walker (2006) showed that bromoenol lactone-mediated inhibition of iPLA2-VIA activity in human endothelial cells blocked endothelial cell growth and inhibited DNA synthesis in a dose-dependent manner. These effects were reversed upon the exogenous addition of arachidonic acid. iPLA2-VIA activity was required for expression of the cyclin A (see CCNA1; 604036)/CDK2 (116953) complex, and thus inhibition of iPLA2-VIA blocked S phase progression and resulted in exit from the cell cycle. Inhibition of iPLA2-VIA-mediated endothelial cell proliferation was sufficient to block angiogenic tubule formation by human endothelial cells cocultured with human dermal fibroblasts. Herbert and Walker (2006) concluded that, by generating arachidonic acid, iPLA2-VIA regulates endothelial cell S phase progression, cell cycle residence, and angiogenesis. They noted that iPLA2-VIA is involved in cell growth and division in other cell types through arachidonic acid-independent regulation of glycerophospholipid metabolism during the cell cycle.
Neurodegeneration with Brain Iron Accumulation 2A and 2B and Karak Syndrome
In studies of 12 families with infantile neuroaxonal dystrophy (INAD, NBIA2A; 256600) and a large consanguineous Pakistani family with neurodegeneration with brain iron accumulation (NBIA2B; 610217), Morgan et al. (2006) mapped a novel INAD locus to 22q12.3-q13.2 (lod score 4.78), with evidence of locus heterogeneity. They also detected linkage to 22q12-q13 in a family with NBIA (lod score 4.65) suggesting allelism. After sequencing 70 of the approximately 100 positional candidate genes, they detected mutations in PLA2G6 in 4 kindreds, including the Pakistani family with NBIA2B and 3 INAD probands (603604.0001-603604.0005). They also identified PLA2G6 mutations in 28 additional probands with INAD and in the original family with Karak syndrome and high basal ganglia iron (see 610217). In all, they identified 44 unique mutations (32 missense, 5 deletions leading to frameshift, 3 nonsense, 2 leading to amino acid deletions without frameshift, 1 splice site, and 1 large deletion). Of the missense mutations, 85% occurred at amino acid positions that are conserved in vertebrates.
In an independent study, Khateeb et al. (2006) identified a homozygous mutation in PLA2G6 in 2 consanguineous Israeli Bedouin kindreds with infantile neuroaxonal dystrophy (NBIA2A). The 3-bp deletion (603604.0004) resulted in the deletion of valine-691.
Gregory et al. (2008) found PLA2G6 mutations in 45 (79%) of 56 patients with INAD1 (NBIA2A) and in 6 (20%) of 23 patients with idiopathic NBIA2B (see, e.g., 603604.0006-603604.0008). No PLA2G6 mutations were found in 11 patients with clinical evidence of INAD, including 5 in whom spheroids were reported on peripheral nerve biopsy. All 28 patients with 2 null mutations or homozygous for any mutation had early onset and rapidly progressive disease. Patients with the less severe phenotype of NBIA tended to have compound heterozygous missense mutations, consistent with residual protein function.
Parkinson Disease 14
In 2 unrelated families with adult-onset dystonia-parkinsonism (PARK14; 612953), Paisan-Ruiz et al. (2009) identified 2 different homozygous mutations in the PLA2G6 gene (R741Q; 603604.0009 and R747W; 603604.0010, respectively). The disorder was characterized by rapidly progressive cognitive decline, bradykinesia, rigidity, and dystonia. None of the 3 affected patients had evidence of brain iron accumulation. The authors emphasized that PLA2G6 mutations should be considered in patients with neurodegeneration even without brain iron on MRI scan.
Magrinelli et al. (2022) reported 14 new patients from 12 families with PARK14 and performed a systematic search for patients with PARK14 in the literature, identifying a total of 86 patients from 68 families, including their own. Parental consanguinity was seen in 55% of families. Homozygosity for mutations in the PLA2G6 gene was seen in 46/86 (53.5%), with compound heterozygosity in 40/86 (46.5%). A total of 54 mutations in PLA2G6 have been associated with parkinsonism, including 4 novel variants in the newly reported patients. Among the 54 mutations, 44 were missense, 2 were in-frame deletions, 4 were splicing, 2 were nonsense, and 2 were frameshift mutations. The most commonly observed mutations were D331Y (603604.0016), seen in 17 families, mainly from China and Taiwan, and R741Q (603604.0009), seen in 12 families from India, Pakistan, and Saudi Arabia.
In a systematic review of 86 patients from 68 families with PARK14, Magrinelli et al. (2022) found that most mutations were nontruncating, which might be less detrimental to protein function than the truncating mutations involved with infantile neuroaxonal dystrophy. Based on limited biochemical and enzymatic studies, the authors suggested that mutations associated with NBIA2A and NBIA2B result in loss of enzyme activity, whereas those associated with PARK14 do not impair phospholipase or lysophospholipase catalytic activity.
Bao et al. (2004) obtained Ipla2-beta-null mice at a mendelian ratio. They found that spermatozoa from Ipla2-beta -/- mice had reduced motility and impaired ability to fertilize mouse oocytes in vitro and in vivo. Female Ipla2-beta -/- mice had nearly normal fertility.
Ramanadham et al. (2008) found that Ipla2-beta-null mice had cortical bone size, trabecular bone volume, bone mineralizing surfaces, and bone strength similar to wildtype mice at 3 months of age. Both groups showed declines in these measures with age, but the decline was more pronounced in Ipla2-beta-null mice. The lower bone mass in Ipla2-beta-null mice was accompanied by an increase in bone marrow fat. Relative to wildtype mice, undifferentiated bone marrow stromal cells from knockout mice expressed higher levels of Pparg (601487) and lower levels of Runx2 (600211) mRNA, and these changes correlated with increased adipogenesis and decreased osteogenesis in bone marrow stromal cells in knockout mice.
Malik et al. (2008) found that Pla2g6-null mice developed age-dependent neurologic impairment that was evident in rotarod, balance, and climbing tests by 13 months of age. Neuropathologic analysis showed numerous spheroids in the brain similar to those observed in human INAD. Spheroids contained tubulovesicular membranes and stained strongly with anti-ubiquitin antibodies. Onset of motor impairment correlated with increased spheroids throughout the neuropil in nearly all brain regions.
In a proband with classic infantile neuroaxonal dystrophy (NBIA2A; 256600), Morgan et al. (2006) identified a 2370T-G transversion in exon 17 of the PLA2G6 gene that was predicted to result in a premature termination in the protein (tyr790 to stop; Y790X). The parents were known to be consanguineous and the mutation was present in homozygous state. The presence of spheroids had been demonstrated.
In a large consanguineous Pakistani family with neurodegeneration with brain iron accumulation-2B (NBIA2B; 610217), Morgan et al. (2006) identified homozygosity for a missense mutation in exon 12 of the PLA2G6 gene, a 1634A-C transversion that resulted in a lys545-to-thr substitution (K545T).
In a case of classic infantile neuroaxonal dystrophy (NBIA2A; 256600), Morgan et al. (2006) described a 929T-A transversion in exon 7 of the PLA2G6 gene, predicted to result in a val310-to-glu (V310E) amino acid change in the protein. The mutation was present in homozygous state.
In a case of classic infantile neuroaxonal dystrophy (NBIA2A; 256600), Morgan et al. (2006) found a 3-bp deletion in exon 15 of the PLA2G6 gene, 2070_2072delTGT, resulting in deletion of val691 from the protein (V691del). The mutation was present in homozygous state, or possibly hemizygous state because of deletion of 1 allele.
In a consanguineous Bedouin kindred with cases of infantile neuroaxonal dystrophy in 3 separate sibships and in another kindred with a single affected individual, Khateeb et al. (2006) found the same 3-nucleotide deletion. The mutation was also found in heterozygosity in a single individual among 300 unrelated Bedouin controls. Both affected families and the unrelated carrier had the same haplotype surrounding the mutation.
In the original family with Karak syndrome (see 610217), Morgan et al. (2006) detected homozygosity for a C-to-T transition at nucleotide 1894 in exon 14 of the PLA2G6 gene that resulted in a substitution of trp for arg at codon 632 (R632W).
In 4 patients with infantile neuroaxonal dystrophy (NBIA2A; 256600), Gregory et al. (2008) identified a homozygous 2370T-G transversion in the PLA2G6 gene, resulting in a tyr790-to-ter (Y790X) substitution. The INAD1 phenotype was characterized by early onset of psychomotor regression with truncal hypotonia and rapid progression to tetraparesis.
Neurodegeneration with Brain Iron Accumulation 2A
In a patient with infantile neuroaxonal dystrophy (NBIA2A; 256600), Gregory et al. (2008) identified a homozygous 2-bp deletion (2370delTG) in the PLA2G6 gene, which resulted in premature termination at codon 790 similar to the Y790X mutation (603604.0006).
Neurodegeneration with Brain Iron Accumulation 2B
In a patient with neurodegeneration with brain iron accumulation-2B (NBIA2B; 610217), Gregory et al. (2008) identified compound heterozygosity for the 2370delTG mutation and a 238G-A transition, resulting in an ala80-to-thr (A80T; 603604.0007) substitution. The patient presented at 3 years of age with toe walking and lower extremity spasticity. She developed optic atrophy and became nonambulatory by 5 years of age with dystonia and dysarthria, progressing to profound sensorimotor impairment by age 9 years. She died at age 23 years. Postmortem examination showed neuronal loss, axonal swelling, and Lewy bodies and neurofibrillary tangles.
For discussion of the ala80-to-thr (A80T) mutation in the PLA2G6 gene that was found in compound heterozygous state in a patient with neurodegeneration with brain iron accumulation-2B (NBIA2B; 610217) by Gregory et al. (2008), see 603604.0007.
In 2 affected first cousins from a large consanguineous Indian kindred segregating adult-onset dystonia-parkinsonism (PARK14; 612953), Paisan-Ruiz et al. (2009) identified a homozygous 2222G-A transition in the PLA2G6 gene, resulting in an arg741-to-gln (R741Q) substitution in a conserved residue. Both had onset at age 26 years of a rapidly progressive neurodegenerative disorder characterized by rapid cognitive decline, bradykinesia, tremor and imbalance, eventually leading to loss of mobility. Although Paisan-Ruiz et al. (2009) noted that brain MRI showed no evidence of brain iron accumulation, Gregory et al. (2009) stated that this disorder could be considered under the umbrella designation of atypical neurodegeneration with brain iron accumulation (NBIA).
In a Pakistani man, born of consanguineous parents, with adult-onset dystonia-parkinsonism (PARK14; 612953), Paisan-Ruiz et al. (2009) identified a homozygous 2239C-T transition in the PLA2G6 gene, resulting in an arg747-to-trp (R747W) substitution in a conserved region. The patient had onset at age 18 years of rapid cognitive decline with personality changes, foot dystonia, parkinsonism, and spasticity. Although Paisan-Ruiz et al. (2009) noted that brain MRI showed no evidence of brain iron accumulation, Gregory et al. (2009) stated that this disorder could be considered under the umbrella designation of atypical neurodegeneration with brain iron accumulation (NBIA).
In 3 Japanese patients, including 2 sibs, with early-onset Parkinson disease-14 (PARK14; 612953), Yoshino et al. (2010) identified compound heterozygosity for 2 mutations in the PLA2G6 gene. All 3 patients carried a 1904G-A transition, resulting in an arg635-to-gln (R635Q) substitution in the catalytic domain. The 2 sibs also had a heterozygous 1354C-T transition, resulting in a gln452-to-ter (Q452X; 603604.0012) substitution, and the third unrelated patient had a heterozygous 216C-A transversion, resulting in a phe72-to-leu (F72L; 603604.0013) substitution. Haplotype analysis suggested a founder effect for the R635Q mutation. All 3 patients had onset before age 30 years of L-DOPA-responsive parkinsonism with varying degrees of cognitive decline and frontotemporal lobar atrophy. Brain MRI of 1 patient showed iron accumulation in the substantia nigra and striatum. None of the parents with heterozygous mutations had signs of the disorder.
For discussion of the gln452-to-ter (Q452X) mutation in the PLA2G6 gene that was found in compound heterozygous state in 2 sibs with early-onset Parkinson disease-14 (PARK14; 612953) by Yoshino et al. (2010), see 603604.0011.
For discussion of the phe72-to-leu (F72L) mutation in the PLA2G6 gene that was found in compound heterozygous state in a patient with early-onset Parkinson disease-14 (PARK14; 612953) by Yoshino et al. (2010), see 603604.0011.
In a patient with infantile neuroaxonal dystrophy (NBIA2A; 256600), Tonelli et al. (2010) identified compound heterozygosity for 2 mutations in the PLA2G6 gene: a 6.6-kb deletion from intron 4 to 6, resulting in an in-frame deletion and removal of exons 5 and 6 and a large portion of the ankyrin repeats motif, and a 109C-T transition in exon 2 resulting in an arg37-to-ter (R37X; 603604.0015) substitution. Analysis of the deletion junction in the first mutation showed that both breakpoints occurred within AluY sequences, suggesting that the deletion was likely mediated by nonallelic homologous recombination (NAHR). The mutations were predicted to result in an almost complete lack of enzyme activity, although a gain of function could not be excluded. The patient had a severe and rapidly progressive disease course, with onset before age 12 months, hypotonia, severe developmental delay with mental retardation, and no eye contact. Spastic tetraparesis developed by age 18 months. Skin biopsy showed axonal spheroids. Although brain iron accumulation was not present, MRI at age 20 months showed hyperintensities on T2-weighted imaging in the caudate and putamen, suggesting an early degeneration process. Brain MRI at age 3 years showed cerebellar cortical atrophy.
For discussion of the arg37-to-ter (R37X) mutation in the PLA2G6 gene that was found in compound heterozygous state in a patient with infantile neuroaxonal dystrophy (NBIA2A; 256600) by Tonelli et al. (2010), see 603604.0014.
In a Chinese man, born of consanguineous parents, with early-onset Parkinson disease (PARK14; 612953), Shi et al. (2011) identified a homozygous 991G-T transversion in the PLA2G6 gene, resulting in an asp331-to-tyr (D331Y) substitution. The mutation was not found in 300 control individuals. The patient developed foot dragging and difficulty walking at age 37 years. Symptoms progressed to include masked facies, bradykinesia, and rigidity, but no atypical features. He had initial good response to L-DOPA treatment, but developed dyskinesias. Brain MRI excluded iron deposition. PET scan showed significant reduction in DAT binding in the basal ganglia. In vitro functional expression studies in HEK293 cells showed that the mutant PLA2G6 protein had about 30% residual activity. The patient's clinically unaffected 34-year-old sister was also homozygous for the mutation, and PET scan showed some loss of binding. The patient was identified in a cohort of 12 Chinese families with early-onset parkinsonism who were screened for PLA2G6 mutations; none of the other 11 families carried a PLA2G6 mutation.
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