Alternative titles; symbols
HGNC Approved Gene Symbol: PISD
SNOMEDCT: 1284851009;
Cytogenetic location: 22q12.2 Genomic coordinates (GRCh38): 22:31,618,491-31,662,564 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q12.2 | Liberfarb syndrome | 618889 | Autosomal recessive | 3 |
Phosphatidylserine decarboxylases (PSDs; EC 4.1.1.65) catalyze the formation of phosphatidylethanolamine (PE) by decarboxylation of phosphatidylserine (PS). Type I PSDs, such as PISD, are targeted to the inner mitochondrial membrane by an N-terminal targeting sequence. PISD also contains a conserved LGST motif that functions as an autocatalytic cleavage site where the proenzyme is split into mature alpha and beta subunits (Schuiki and Daum, 2009).
Kuge et al. (1991) cloned Pisd, which they called Pssc, from Chinese hamster ovary cells. The deduced protein contains at least 370 amino acids. Northern blot analysis detected a transcript of about 2.4 kb.
Using real-time PCR, Steenbergen et al. (2005) found that Pisd was expressed in all mouse tissues examined, with highest expression in testis and liver. Expression was lower in embryonic and young mice compared with adult mice. Beta-galactosidase (GLB1; 611458) staining detected high Pisd expression in embryonic heart and in Sertoli cells of adult testis.
By PCR of a placenta cDNA library, Forbes et al. (2007) cloned human PISD. The full-length proenzyme contains 409 amino acids and is self-processed into an active heterodimer.
By genomic sequence analysis, Dunham et al. (1999) mapped the PISD gene to chromosome 22q12.
By assaying membranes prepared from transfected human embryonic kidney cells, Forbes et al. (2007) confirmed that human PISD was catalytically active, and they identified several chemical inhibitors of PISD activity.
Schuiki and Daum (2009) reviewed PSDs and their role in lipid metabolism.
In in vitro and in vivo studies in mice and humans, Keckesova et al. (2017) demonstrated that the mitochondrial protein LACTB (608440) potently inhibits the proliferation of breast cancer cells. Its mechanism of action involves alteration of mitochondrial lipid metabolism and differentiation of breast cancer cells. This is achieved, at least in part, through reduction of the levels of mitochondrial PISD, which is involved in the synthesis of mitochondrial phosphatidylethanolamine. Keckesova et al. (2017) concluded that their observations uncovered a novel mitochondrial tumor suppressor and demonstrated a connection between mitochondrial lipid metabolism and the differentiation program of breast cancer cells.
In 2 sets of brothers from 2 unrelated consanguineous families with Liberfarb syndrome (LIBF; 618889), Peter et al. (2019) identified homozygosity for a 10-bp deletion in the PISD gene (612770.0001) that segregated with disease in both families. Targeted Sanger sequencing of DNA from the patient originally reported by Liberfarb et al. (1986) (patient 5, LIB-001), extracted from a paraffin-embedded surgical biopsy of the esophagus, confirmed the presence of the same 10-bp deletion. The 3 patients, from families that originated from Portugal, Brazil, and the Azores, shared a common haplotype around the PISD gene, consistent with a common ancestor approximately 5 generations earlier.
In an affected girl and boy from unrelated Indian families with an 'unclassifiable' form of spondyloepimetaphyseal dysplasia, Girisha et al. (2019) identified homozygosity for a missense mutation in the PISD gene (C266Y; 612770.0002) that segregated with disease and was not found in controls or the gnomAD database. Analysis of regions of homozygosity indicated remote consanguinity between the 2 families.
In 2 sisters with progressive short stature and skeletal dysplasia, Zhao et al. (2019) identified compound heterozygosity for a missense mutation (R277Q; 612770.0003) and a splicing mutation (612770.0004) in the PISD gene.
Steenbergen et al. (2005) found that Pisd -/- mice died between embryonic days 8 and 10. In 8-day-old Pisd -/- embryos, there were no extra-embryonic components, such as placenta or amnion, and the embryo was in direct contact with maternal blood. A large number of mitochondria in Pisd -/- embryos were aberrantly shaped, although the inner and outer membranes were present, and cristae were clearly visible. Mitochondria from embryonic fibroblasts were fragmented and rounded, with irregular diameter, and they were widely dispersed throughout the cell rather than being concentrated near the nucleus. Pisd +/- mice appeared normal, exhibited normal vitality, and had the same phospholipid composition of liver, testis, and brain as wildtype mice. However, the amount of CTP-phosphoethanolamine cytidylyltransferase (PCYT2; 602679) protein, which synthesizes PE through an alternative pathway in the endoplasmic reticulum, was elevated, and the enzymatic activity of Pcyt2 was 100% higher in live homogenates from Pisd +/- mice compared with wildtype.
In 2 sets of brothers from 2 unrelated consanguineous families with Liberfarb syndrome (LIBF; 618889), from continental Portugal (family 1; patients PMO1432 and PMO1433) and Brazil (family 2; patients PMO3433 and PMO3434), (603213), Peter et al. (2019) identified homozygosity for a 10-bp deletion (c.904-12_904-3delCTATCACCAC, NM_014338.3) in intron 8 of the PISD gene that segregated fully with disease in both families. Using DNA extracted from a surgical specimen from the patient originally reported by Liberfarb et al. (1986) (patient 5, LIB-001), whose parents originated from the Azores, Peter et al. (2019) confirmed the presence of the same 10-bp deletion. Families 1 and 2 shared a common haplotype, the size of which corresponded to approximately 9.92 meioses, suggesting that the Portuguese and Brazilian patients had a common ancestor about 5 generations earlier. Minigene-based splicing experiments in HEK293T cells revealed that the deletion prevents proper recognition of the natural acceptor splice site, with production of both correctly spliced mRNA and transcripts retaining all of intron 8; the latter event creates a premature stop codon within the intron. Quantitative PCR analysis showed that the proportion of correctly spliced mRNA transcripts from plasmids bearing the deletion was only 5.7% compared to transcripts from plasmids carrying the wildtype minigene.
In an affected 3-year-old girl (P1) and 9-year-old boy (P2) from unrelated Indian families with Liberfarb syndrome (LIBF; 618889), Girisha et al. (2019) identified homozygosity for a c.797G-A transition (c.797G-A, NM_178022.1) in the PISD gene, resulting in a cys266-to-tyr (C266Y) substitution at a highly conserved residue. The unaffected parents were heterozygous for the mutation, which was not found in an in-house database of 475 control exomes from Indian families with rare mendelian disorders, or in the gnomAD database. Analysis of exome data and regions of homozygosity revealed that both probands shared a common haplotype around the PISD gene, indicating remote consanguinity. Patient-derived fibroblasts showed fragmented mitochondrial morphology around the nucleus compared to controls. Treatment of patient cells with MG-132 or staurosporine to induce activation of the intrinsic apoptosis pathway revealed significantly decreased cell viability with increased caspase-3 (CASP3; 600636) and caspase-7 (CASP7; 601761) activation. Ethanolamine supplementation largely restored cell viability and reduced CASP3/7 activation in MG-132-stressed patient cells.
In transiently transfected HEK cells, Zhao et al. (2019) observed that the C266Y variant markedly reduced autocatalytic processing of the PISD protein, which is required for its activity.
In 2 sisters with Liberfarb syndrome (LIBF; 618889), Zhao et al. (2019) identified compound heterozygosity for a c.830G-A transition (c.830G-A, NM_001326411.1) in exon 6 of the PISD gene, resulting in an arg277-to-gln (R277Q) substitution at a highly conserved residue, and a splicing mutation (c.697+5G-A) in intron 5 (612770.0004). Their unaffected mother was heterozygous for the splicing variant, which was not found in the gnomAD, ESP, or 1000 Genomes Project databases. DNA analysis was not reported for their father. The missense mutation was present at low frequency in the gnomAD database (0.01923%), in European-American populations in the ESP database (0.03%), and in the 1000 Genomes Project database (0.02%). Functional analysis of patient fibroblasts showed an approximately 50% reduction in conversion of phosphatidylserine to phosphatidylethanolamine (PE) compared to wildtype cells. In addition, patient fibroblasts demonstrated evidence of mitochondrial dysfunction, with more fragmented mitochondrial networks, enlarged lysosomes, decreased maximal oxygen consumption rates, and increased sensitivity to 2-deoxyglucose compared to wildtype cells. Replenishment of the mitochondrial pool of PE with lyso-PE, as well as transfection with wildtype PISD, restored mitochondrial and lysosomal morphology in patient fibroblasts. Analysis of cDNA from patient fibroblasts revealed a minor PCR band that was not present in the control; the alternative splicing product was more abundant after treatment with cycloheximide, indicating that it was subject to nonsense-medicated decay. A similar pattern of missplicing was observed in cDNA generated from the mother's peripheral blood RNA, confirming that the c.697+5G-A variant altered splicing. Functional analysis of the R277Q variant in yeast and in transfected HEK cells showed severely impaired autocatalytic processing of the PISD protein, which is required for its activity.
For discussion of the splicing mutation (c.697+5G-A, NM_001326411.1) in intron 5 of the PISD gene that was found in compound heterozygous state in 2 sisters with Liberfarb syndrome (LIBF; 618889) by Zhao et al. (2019), see 612770.0003.
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Girisha, K. M., von Elsner, L., Neethukrishna, K., Muranjan, M., Shukla, A., Bhavani, G. S., Nishimura, G., Kutsche, K., Mortier, G. The homozygous variant c.797G-A/p.(cys266tyr) in PISD is associated with a spondyloepimetaphyseal dysplasia with large epiphyses and disturbed mitochondrial function. Hum. Mutat. 40: 299-309, 2019. [PubMed: 30488656] [Full Text: https://doi.org/10.1002/humu.23693]
Keckesova, Z., Donaher, J. L., De Cock, J., Freinkman, E., Lingrell, S., Bachovchin, D. A., Bierie, B., Tischler, V., Noske, A., Okondo, M. C., Reinhardt, F., Thiru, P., Golub, T. R., Vance, J. E., Weinberg, R. A. LACTB is a tumour suppressor that modulates lipid metabolism and cell state. Nature 543: 681-686, 2017. [PubMed: 28329758] [Full Text: https://doi.org/10.1038/nature21408]
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Peter, V. G., Quinodoz, M., Pinto-Basto, J., Sousa, S. B., Di Gioia, S. A., Soares, G., Leal, G. F., Silva, E. D., Gobert, R. P., Miyake, N., Matsumoto, N., Engle, E. C., Unger, S., Shapiro, F., Superti-Furga, A., Rivolta, C., Campos-Xavier, B. The Liberfarb syndrome, a multisystem disorder affecting eye, ear, bone, and brain development, is caused by a founder pathogenic variant in the PISD gene. Genet. Med. 21: 2734-2743, 2019. [PubMed: 31263216] [Full Text: https://doi.org/10.1038/s41436-019-0595-x]
Schuiki, I., Daum, G. Phosphatidylserine decarboxylases, key enzymes of lipid metabolism. Life 61: 151-162, 2009. [PubMed: 19165886] [Full Text: https://doi.org/10.1002/iub.159]
Steenbergen, R., Nanowski, T. S., Beigneux, A., Kulinski, A., Young, S. G., Vance, J. E. Disruption of the phosphatidylserine decarboxylase gene in mice causes embryonic lethality and mitochondrial defects. J. Biol. Chem. 280: 40032-40040, 2005. [PubMed: 16192276] [Full Text: https://doi.org/10.1074/jbc.M506510200]
Zhao, T., Goedhart, C. M., Sam, P. N., Sabouny, R., Lingrell, S., Cornish, A. J., Lamont, R. E., Bernier, F. P., Sinasac, D., Parboosingh, J. S., Care4Rare Canada Consortium, Vance, J. E., Claypool, S. M., Innes, A. M., Shutt, T. E. PISD is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes. Life Sci. Alliance 2: e201900353, 2019. Note: Electronic Article. [PubMed: 30858161] [Full Text: https://doi.org/10.26508/lsa.201900353]