Alternative titles; symbols
HGNC Approved Gene Symbol: PNPLA4
Cytogenetic location: Xp22.31 Genomic coordinates (GRCh38): X:7,898,247-7,927,724 (from NCBI)
The PNPLA4 gene encodes a protein with both triacylglycerol lipase and transacetylase activities (summary by Kohda et al., 2016).
Lee et al. (1994) isolated a gene they designated GS2 from a CpG island located approximately midway between the steroid sulfatase (STS; 300747) and the Kallmann syndrome (KAL1; 300836) genes on distal Xp. DNA sequencing of a GS2 cDNA clone demonstrated an open reading frame for a basic protein of 253 amino acid residues and an isoelectric point of 9.8. A polymorphic CT dinucleotide repeat was found in the 3-prime untranslated region. The GS2 gene was expressed in all human tissues examined, including heart, brain, placenta, lung, liver, muscle, kidney, pancreas, and spleen. Several GS2 transcripts, ranging in size from 1.1 to 5.8 kb, were found among different tissues, suggesting tissue-specific processing of the GS2 transcript.
By immunofluorescence studies, Kohda et al. (2016) found mitochondrial localization of the PNPLA4 gene.
Jenkins et al. (2004) found that purified recombinant PNPLA3 (609567), PNPLA2 (609059), and PNPLA4 expressed in insect cells showed abundant triacylglycerol lipase activity. The recombinant enzymes also showed acylglycerol transacylase activity by transferring the acyl donor mono-olein to mono-olein or diolein acceptors to form diolein and triolein, respectively.
Gao and Simon (2007) showed that in 293T cells transfected PNPLA4 transferred fatty acid from triglyceride to retinol, hydrolyzed retinylesters, and generated 1,3-diacylglycerol from triglycerides. Since retinoid and triglyceride metabolites are transcription factor ligands, they suggested that PNPLA4 may regulate epidermal homeostasis.
Characterization of GS2 genomic clones revealed that the gene consists of 7 exons spanning over 26 kb, with a CpG island located in the first intron.
Lee et al. (1994) mapped the GS2 gene approximately midway between the STS and KAL1 genes on distal Xp. GS2 is transcribed toward Xpter, in the same direction as KAL1 but opposite that of STS.
Stumpf (2020) mapped the PNPLA4 gene to chromosome Xp22.31 based on an alignment of the PNPLA4 sequence (GenBank BC020746) with the genomic sequence (GRCh38).
Associations Pending Confirmation
For discussion of a possible association between variation in the PNPLA4 gene and combined oxidative phosphorylation deficiency (COXPD; see 609060), see 300102.0001.
This variant is classified as a variant of unknown significance because its contribution to combined oxidative phosphorylation deficiency (COXPD; see 609060) has not been confirmed.
In a patient (Pt712) with lethal COXPD, Kohda et al. (2016) identified a hemizygous c.559C-T transition (c.559C-T, NM_001142389) in the PNPLA4 gene, resulting in an arg187-to-ter (R187X) substitution. The variant, which was found by high-throughput exome sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. The variant was filtered against the dbSNP (build 137), Exome Sequencing Project, and ExAC databases. Patient fibroblasts showed loss of the PNPLA4 protein. Under low glucose medium, patient fibroblasts showed reduced assembly of mitochondrial respiratory complexes I, III, and IV; expression of wildtype PNPLA4 recovered complex III and IV assembly under low glucose medium conditions. Clinical details were limited, but the patient was initially diagnosed with complex IV deficiency. The patient was part of a large cohort of 142 patients with childhood-onset mitochondrial respiratory chain complex deficiencies who underwent genetic studies.
Gao, J. G., Simon, M. A comparative study of human GS2, its paralogues, and its rat orthologue. Biochem. Biophys. Res. Commun. 360: 501-506, 2007. [PubMed: 17603008] [Full Text: https://doi.org/10.1016/j.bbrc.2007.06.089]
Jenkins, C. M., Mancuso, D. J., Yan, W., Sims, H. F., Gibson, B., Gross, R. W. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J. Biol. Chem. 279: 48968-48975, 2004. [PubMed: 15364929] [Full Text: https://doi.org/10.1074/jbc.M407841200]
Kohda, M., Tokuzawa, Y., Kishita, Y., Nyuzuki, H., Moriyama, Y., Mizuno, Y., Hirata, T., Yatsuka, Y., Yamashita-Sugahara, Y., Nakachi, Y., Kato, H., Okuda, A., and 23 others. A comprehensive genomic analysis reveals the genetic landscape of mitochondrial respiratory chain complex deficiencies. PLoS Genet. 12: e1005679, 2016. Note: Electronic Article. [PubMed: 26741492] [Full Text: https://doi.org/10.1371/journal.pgen.1005679]
Lee, W.-C., Salido, E., Yen, P. H. Isolation of a new gene GS2 (DXS1283E) from a CpG island between STS and KAL1 on Xp22.3. Genomics 22: 372-376, 1994. [PubMed: 7806223] [Full Text: https://doi.org/10.1006/geno.1994.1397]
Stumpf, A. M. Personal Communication. Baltimore, Md. 07/28/2020.