Alternative titles; symbols
HGNC Approved Gene Symbol: PLA2G4A
SNOMEDCT: 1172901009;
Cytogenetic location: 1q31.1 Genomic coordinates (GRCh38): 1:186,828,949-186,988,981 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1q31.1 | Gastrointestinal ulceration, recurrent, with dysfunctional platelets | 618372 | Autosomal recessive | 3 |
Cytosolic phospholipase A2 (PLA2; EC 3.1.1.4) catalyzes the release of arachidonic acid from membrane phospholipids. Arachidonic acid in turn serves as precursor for a wide spectrum of biologic effectors, collectively known as eicosanoids, that are involved in hemodynamic regulation, inflammatory responses, and other cellular processes (summary by Tay et al., 1995). (Eicosanoids are lipid mediators of inflammation; they include a variety of compounds (prostaglandins, thromboxanes, leukotrienes, hydroxy- and epoxy-fatty acids, lipoxins, and isoprostanes) that are derived from the ubiquitous 20-carbon atom arachidonate (20 in Greek is 'eicosa') and a few similar polyunsaturated fatty acids (summary by De Caterina and Zampolli, 2004).)
Dennis (1994) reviewed various types of PLA2. The best characterized is the group II PLA2 originally isolated from human synovial fluid (i.e., PLA2G2A; 172411). Groups I (human pancreatic, PLA2G1B (172410); also found in cobras and kraits), II (synovial; also found in rattlesnakes and vipers), and III (forms of which were described in bee and lizard) are secreted; group IV is cytosolic.
Cytosolic phospholipase A2 described here (see GenBank AF065216) is distinct from the synovial phospholipase A2 (PLA2G2A; 172411); it has a large molecular weight; is DTT-insensitive; is activated at a nanomolar to micromolar calcium concentration range, which prevails in the cytosol; and is arachidonic acid-specific at the sn-2 position (Skorecki, 1995). PLA2B, the synovial phospholipase A2 described by Seilhamer et al. (1989), is a small molecular weight enzyme that is DTT-sensitive. PLA2B is secreted from cells, active in the micromolar to millimolar calcium concentration range that prevails in the extracellular medium, and active in inflammatory exudates.
Sharp et al. (1991) amplified PLA2G4A by PCR with human U937 monoblast cells, using degenerate primers designed from the purified sequenced protein. They cloned PLA2G4A cDNA from a U937 library screened with the PCR product. The deduced 749-amino acid protein has a predicted molecular mass of 85 kD and contains several potential PKC and tyrosine kinase phosphorylation sites. Northern blot analysis detected an approximately 3-kb transcript in U937 cells. Western blot analysis of U937 cells revealed that PLA2G4 migrates with an apparent molecular mass of 100 kD.
Tay et al. (1995) mapped the PLA2G4A gene to rat chromosome 13 by PCR-based intercross genotyping and to human 1q25 by fluorescence in situ hybridization. The gene encoding the enzyme prostaglandin-endoperoxide synthase-2, also known as cyclooxygenase-2 (PTGS2; 600262), had previously been mapped to the same chromosomal region, raising the possibility of coordinate regulation. PTGS2 is downstream of cytosolic phospholipase A2 in the biochemical pathway for eicosanoid production.
Dessen et al. (1999) reported the x-ray crystal structure of human PLA2G4A at 2.5-angstrom resolution. The structure provided insight into the origin of arachidonate selectivity and interfacial activation, clarified the roles of ser228, asp549, and arg200, and revealed the interplay between the C2 and catalytic domains.
By site-directed mutagenesis and biochemical analysis of the recombinant protein, Sharp et al. (1994) determined that ser228 participates in the catalytic mechanism of cPLA2 and that both the phospholipase A2 and the lysophospholipase activities are catalyzed by the same active site residue(s).
PLA2G4A, the cytosolic phospholipase A2, appears to subserve transmembrane signaling responses to extracellular ligands (Skorecki, 1995).
Sheridan et al. (2001) found that cPLA2 interacts with both splice variants of HTATIP (601409), a protein that was originally isolated as an HIV-1 TAT-interactive protein. In transfection experiments, they found that cPLA2 and HTATIP coimmunoprecipitate and colocalize. Using serum withdrawal to induce growth arrest and apoptosis in mouse renal mesangial cells, Sheridan et al. (2001) found cytosolic to nuclear translocation of endogenous complexes correlated with onset of apoptosis. CPLA2 and HITATIP synergistically induced arachidonic acid production following serum withdrawal.
In a 45-year-old man with recurrent gastrointestinal ulceration with dysfunctional platelets (GURDP; 618372), Adler et al. (2008) identified compound heterozygous missense mutations in the PLA2G4A gene (S111P, 600522.0001 and R485H, 600522.0002).
In a brother and sister from a large Sardinian family with GURDP, Faioni et al. (2014) identified a homozygous missense mutation in the PLA2G4A gene (D575H; 600522.0003). Patient platelets showed normal PLA2G4A mRNA levels, but undetectable protein levels, suggesting instability of the mutant protein and consistent with a complete loss of function. Analysis of 35 other family members showed that 14 (40%) were heterozygous for the variant and 21 (60%) were homozygous wildtype. Heterozygotes for the variant did not have a bleeding diathesis, but had a relatively high prevalence of duodenal ulcers at a young age (less than 40 years).
In a Serbian brother and sister with GURDP, Brooke et al. (2014) identified a homozygous 4-bp deletion in the PLA2G4A gene (600522.0004). The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Gastrointestinal mucosal tissue and peripheral blood cells from the patients showed complete absence of the PLA2G4A protein.
Haq et al. (2003) generated mice deficient in PLA2G4A by targeted disruption. Heart size was larger in knockout mice compared to wildtype littermates, and both heart and skeletal myocyte cross-sectional area were significantly greater in knockout mice. Haq et al. (2003) found that cytosolic PLA2, the protein product of the PLA2G4A gene, is a negative regulator of growth, specifically of striated muscle. They showed that normal growth of skeletal muscle, as well as normal and pathologic stress-induced hypertrophic growth of the heart, were exaggerated in Pla2g4a -/- mice. The mechanism underlying this phenotype is that cytosolic PLA2 negatively regulates insulin-like growth factor-1 (IGF1; 147440) signaling. Absence of cytosolic PLA2 leads to sustained activation of the IGF1 pathway, which results from the failure of 3-phosphoinositide-dependent protein kinase-1 (PDK1; 605213) to recruit and phosphorylate protein kinase C-zeta (176982), the negative regulator of IGF1 signaling. Arachidonic acid restores activation of PKC-zeta, correcting the exaggerated IGF1 signaling. Haq et al. (2003) concluded that cytosolic PLA2 and arachidonic acid regulate striated muscle growth by modulating multiple growth-regulatory pathways.
Ichinose et al. (2002) found that Pla2g4a-null mice were less able than wildtype mice to maintain systemic oxygenation during left main stem bronchus occlusion, and they did not increase pulmonary vascular resistance during occlusion, as did wildtype mice. Inhibition of cyclooxygenase or nitric oxide synthase, as well as breathing 10% oxygen for 3 weeks, restored hypoxic pulmonary vasoconstriction in mutant mice. Ichinose et al. (2002) concluded that Pla2g4a contributes to the murine pulmonary vasoconstrictor response to hypoxia and that augmenting pulmonary vascular tone restores vasoconstriction in the absence of Pla2g4a activity.
Hegen et al. (2003) generated cPla2-alpha -/- mice on a DBA/1LacJ background susceptible to collagen-induced arthritis (CIA), a mouse model of rheumatoid arthritis (180300). The mutant mice were much less likely to develop CIA than wildtype mice, although there was no difference in their anti-collagen antibody levels. Hegen et al. (2003) concluded that cPLA2-alpha plays a critical role in CIA pathogenesis.
After contusive spinal cord injury in rats, Liu et al. (2006) found increased overall Pla2 activity and markedly increased cytosolic Pla2 expression (6- to 7-fold) mainly within neurons and oligodendrocytes of the spinal cord. In vitro, endogenous Pla2 induced spinal cord neuronal death, which was reversed by the Pla2 inhibitor mepacrine. Microinjection of Pla2 into spinal cord in vivo resulted in confined demyelination and later diffuse tissue necrosis, as well as increased inflammation, oxidation, and tissue damage with corresponding electrophysiologic and behavioral impairment. Liu et al. (2006) suggested that Pla2 may be a converging molecule that mediates pathogenesis of multiple injury pathways in spinal cord injury and that blocking its action may reduce tissue damage.
In a 45-year-old man with recurrent gastrointestinal ulceration with dysfunctional platelets (GURDP; 618372), Adler et al. (2008) identified compound heterozygosity for a c.331T-C transition and a c.1454G-A transition in the PLA2G4A gene, resulting in a ser111-to-pro (S111P) and an arg485-to-his (R485H; 600522.0002) substitution, respectively. The patient's asymptomatic mother and sister, who had intermediate reductions in eicosanoid biosynthesis, were heterozygous for the S111P and R485H mutations, respectively.
For discussion of the arg485-to-his (R485H) mutation in the PLA2G4A gene that was found in compound heterozygous state in a patient with recurrent gastrointestinal ulceration with dysfunctional platelets by Adler et al. (2008), see 600522.0001.
In a brother and sister from a large Sardinian family with recurrent gastrointestinal ulceration with dysfunctional platelets (GURDP; 618372), Faioni et al. (2014) identified a homozygous c.1723G-C transversion in exon 15 of the PLA2G4A gene, resulting in an asp575-to-his (D575H) substitution at a highly conserved residue in the catalytic domain. Patient platelets showed normal PLA2G4A mRNA levels, but undetectable protein levels, suggesting instability of the mutant protein and consistent with a complete loss of function. Analysis of 35 other family members showed that 14 (40%) were heterozygous for the variant and 21 (60%) were homozygous wildtype. Heterozygotes for the variant did not have a bleeding diathesis, but had a relatively high prevalence of duodenal ulcers at a young age (less than 40 years).
In a Serbian brother and sister with recurrent gastrointestinal ulceration with dysfunctional platelets (GURDP; 618372), Brooke et al. (2014) identified a homozygous 4-bp deletion (g.155574_77delGTAA, GRCh37) in the splice donor site of intron 17 of the PLA2G4A gene, resulting in a frameshift and premature termination (Val707fsTer10). The mutation was predicted to result in the loss of 43 C-terminal residues. The mutation, which was found by a combination of linkage analysis and exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not found in the dbSNP or 1000 Genomes Project databases. Gastrointestinal mucosal tissue and peripheral blood cells from the patients showed complete absence of the PLA2G4A protein.
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