Alternative titles; symbols
HGNC Approved Gene Symbol: PPP1R13L
Cytogenetic location: 19q13.32 Genomic coordinates (GRCh38) : 19:45,379,638-45,406,361 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.32 | Arrhythmogenic cardiomyopathy with variable ectodermal abnormalities | 620519 | Autosomal recessive | 3 |
IASPP is one of the most evolutionarily conserved inhibitors of p53 (TP53; 191170), whereas ASPP1 (606455) and ASPP2 (602143) are activators of p53.
Using a fragment of RELA (164014) in a yeast 2-hybrid screen, followed by PCR of a placenta cDNA library, Yang et al. (1999) isolated a partial cDNA for PPP1R13L, which they called RAI. The deduced 351-amino acid partial protein has a calculated molecular mass of 40 kD. RAI contains 4 consecutive ankyrin repeats and a C-terminal SH3 domain. The C-terminal 223 amino acids share 52% sequence identity with the C terminus of 53BP2 (602143), a p53 (191170)-binding protein. Northern blot analysis detected transcripts of 3.4 and 6 kb. Expression of RAI was high in heart, placenta, and prostate, and was reduced in brain, liver, skeletal muscle, testis, and peripheral blood leukocytes. Fluorescence-tagged RAI transfected into HeLa cells showed a nuclear subcellular distribution, as did RELA.
By searching EST databases using the RAI cDNA reported by Yang et al. (1999), Slee et al. (2004) identified a longer cDNA for PPP1R13L, which they called IASPP. The IASPP cDNA encodes a deduced 828-amino acid protein with a C terminus identical to that of RAI. Western blot analysis detected IASPP at an apparent molecular mass of 100 kD, but RAI was not detected. Immunofluorescence analysis showed endogenous IASPP predominantly in the cytoplasm, with a small amount in the nucleus.
Herron et al. (2005) cloned mouse Ppp1r13L, which they called Nkip1. The deduced 824-amino acid has predicted molecular mass of 98 kD that was confirmed by Western blot analysis.
Gross (2015) mapped the PPP1R13L gene to chromosome 19q13.32 based on an alignment of the PPP1R13L sequence (GenBank BC032298) with the genomic sequence (GRCh38).
By positional cloning, Herron et al. (2005) mapped the mouse Ppp1r13l gene to mouse chromosome 7.
Using a yeast 2-hybrid binding assay, Yang et al. (1999) confirmed interaction between RAI and RELA. RAI did not bind p53, despite sequence similarity with 53BP2. Coimmunoprecipitation experiments of transfected human embryonic kidney cells revealed RAI-RELA interactions within intact cells as well as in vitro. Using luciferase reporter plasmids, Yang et al. (1999) demonstrated that RAI inhibited RELA-induced luciferase gene expression in a dose-dependent manner. RAI had no significant effect on p53-dependent transcription. RAI also inhibited tumor necrosis factor-alpha (TNFA; 191160)-induced nuclear factor kappa-B (NFKB) activation. RAI specifically inhibited the DNA binding activity of RELA when cotransfected into human embryonic kidney cells.
IASPP is an evolutionarily conserved inhibitor of p53; inhibition of IASPP by RNA-mediated interference or antisense RNA in C. elegans or human cells, respectively, induces p53-dependent apoptosis. Moreover, IASPP is an oncoprotein that cooperates with Ras (190020), E1A (see 602700), and E7, but not mutant p53, to transform cells in vitro (Bergamaschi et al., 2003). Increased expression of IASPP also confers resistance to ultraviolet radiation and to cisplatin-induced apoptosis. IASPP expression is upregulated in human breast carcinomas expressing wildtype p53 and normal levels of ASPP (ASPP1, 606455; ASPP2, 602143). On the basis of their findings, Bergamaschi et al. (2003) suggested that inhibition of IASPP could provide an important new strategy for treating tumors expressing wildtype p53.
Bergamaschi et al. (2006) showed that, in addition to the DNA-binding domain, the ASPP family members also bind to the proline-rich region of p53, which contains the most common p53 polymorphism at codon 72 (191170.0005). Furthermore, the ASPP family members, particularly IASPP, bind to and regulate the activity of p53 pro72 more efficiently than that of p53 arg72. Hence, escape from negative regulation by IASPP is a newly identified mechanism by which p53 arg72 activates apoptosis more efficiently than p53 pro72.
Using immunoprecipitation analysis, Slee et al. (2004) showed that both IASPP and RAI interacted with endogenous p53 in a human breast cancer cell line, and both proteins inhibited apoptosis induced by p53 expression. Mutation analysis indicated that the long N-terminal domain of IASPP contains a signal that directs the protein to the cytoplasm.
In a large, multiply consanguineous 7-generation Arab Christian pedigree in which 5 children from 4 sibships had severe dilated cardiomyopathy with woolly hair, erythematous scaly skin, and wedge-shaped teeth (ARCME; 620519), Falik-Zaccai et al. (2017) identified homozygosity for a nonsense mutation in the PPP1R13L gene (Y747X; 607463.0001). The mutation segregated with disease, and homozygosity for the Y747X substitution was also present in 4 fetuses from 1 of the sibships who were aborted due to midline brain, eye, and facial defects. The authors suggested that 2 different disorders might be segregating in this highly inbred pedigree, or alternatively that the midline malformations might be incompletely penetrant.
In 7 children from 5 unrelated families with ARCME, Robinson et al. (2020) identified homozygosity or compound heterozygosity for mutations in the PPP1R13L gene (see, e.g., 607463.0002-607463.0004) that segregated fully with disease and were either not found or present at low minor allele frequency in the gnomAD database.
By trio whole-exome sequencing in a 3-year-old girl of Middle Eastern descent with ARCME and her unaffected first-cousin parents, Henry et al. (2022) identified homozygosity for a 1-bp duplication in the PPP1R13L gene (607463.0005) that segregated with disease and was not found in the gnomAD database.
In a 2-year-old Iranian boy with ARCME, Kalayinia et al. (2022) identified homozygosity for a nonsense mutation in the PPP1R13L gene (Q194X; 607463.0006) that segregated fully with disease in the family.
Herron et al. (2005) identified a novel recessive murine mutation Waved3 (Wa3) that caused open eyelids at birth, wavy coat, and a cardiac defect resulting in severe and rapidly progressive dilated cardiomyopathy. Positional cloning and sequence analysis revealed a 14-bp deletion that removed a splice donor site in Ppp1r13l gene, which they called Nkip1, resulting in a protein lacking the C-terminal SH3 domain. By Northern blot analysis, Nkip1 was detected in mouse skin, heart, testis, and stomach with lower expression in kidney, liver, and lung. In situ hybridization revealed expression in simple and stratified epithelia, including epidermis and hair follicles, the fore stomach, esophagus, bladder epithelium, heart, and endothelia of arteries. Expression analysis of genes known to be regulated by Nfkb revealed that Icam1 (147840) expression was consistently elevated in Wa3-mutant mice.
Falik-Zaccai et al. (2017) knocked down Ppp1r13l in newborn mouse cardiomyocytes and observed that lipopolysaccharide (LPS)-inducible expression of proinflammatory cytokine genes Il1b (147720), Tnfa (TNF; 191160), and Il6 (147620) was higher than in control cardiomyocytes. In addition, mRNA levels of several known dilated cardiomyopathy-associated genes were reduced. Following treatment with LPS for 4 hours, a cohort of genes encoding proinflammatory mediates such as chemokines, cytokines, matrix metalloproteinases, and nitric oxide synthase (see 163731) were upregulated more strongly in the Ppp1r13l-knockdown cells than in controls. RNA-seq analysis confirmed higher inducible expression of genes associated with acute inflammation in the hearts of Ppp1r13l-deficient (Wa3) mice than in controls. The authors suggested that a proinflammatory transcriptional pattern might underlie the adverse cardiac remodeling observed in PPP1R13L-deficient patients.
In 3 deceased children from 3 sibships of a large multiply consanguineous 7-generation Arab Christian pedigree with severe dilated cardiomyopathy and woolly hair, reddened scaly skin, and wedge-shaped teeth (ARCME; 620519), Falik-Zaccai et al. (2017) identified homozygosity for a c.2241C-G transversion in exon 11 of the PPP1R13L gene, resulting in a tyr747-to-ter (Y747X) substitution. Their consanguineous parents were heterozygous for the mutation, which was not found in the dbSNP or 1000 Genomes Project databases. DNA was unavailable from 2 deceased affected sisters or their deceased father, but their mother and maternal grandmother carried the Y747X variant in heterozygosity. In addition, 4 fetuses from 1 of the sibships, who were aborted due to midline brain, eye, and facial defects, were also homozygous for the Y747X mutation. The authors suggested that 2 different disorders might be segregating in this highly inbred pedigree, or alternatively that the midline malformations might be incompletely penetrant. Analysis of DNA markers closely linked to PPP1R13L supported a common founder haplotype in all patients. Among 100 controls from the same village as the family, 11 heterozygous carriers were found; analysis of 100 controls from the Arab Christian community in northern Israel identified 1 carrier, indicating existence of a genetic isolate for the phenotype. PPP1R13L mRNA levels were lower in patient skin-derived fibroblasts compared to age-matched controls, and the IASPP protein was completely absent from patient fibroblasts. Patient fibroblasts and PPP1R13L-knockdown human fibroblasts showed higher expression levels of proinflammatory cytokine genes in response to lipopolysaccharide than control fibroblasts. The hypersensitivity to lipopolysaccharide was NFKB (see 164011)-dependent, and its inducible binding activity to promoters of proinflammatory cytokine genes was elevated in patient fibroblasts.
In a boy (family 1) who died at age 3 years with dilated cardiomyopathy, sparse wiry hair, and dystrophic nails (ARCME; 620519), Robinson et al. (2020) identified compound heterozygosity for mutations in the PPP1R13L gene: a 2-bp del/ins (c.2486_2487delinsTC, NM_001142502.1), causing a frameshift predicted to result in extension of the protein (Ter829PheextTer59), and a 1-bp deletion (c.1610del; 607463.0003), causing a frameshift predicted to result in a premature termination codon (Pro537LeufsTer100). The mutations were confirmed by Sanger sequencing and the unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in the gnomAD database.
For discussion of the 1-bp deletion (c.1610del, NM_001142502.1) in the PPP1R13L gene, causing a frameshift predicted to result premature termination of the protein (Pro537LeufsTer100), that was found in compound heterozygous state in a boy (family 1) who died at age 3 years with arrhythmogenic cardiomyopathy and ectodermal abnormalities (ARCME; 620519) by Robinson et al. (2020), see 607463.0002.
In 2 brothers (family 2) who died at ages 2.5 years and 4.75 years with dilated cardiomyopathy and thin, curly hair (ARCME; 620519), Robinson et al. (2020) identified homozygosity for a 29-bp deletion (c.736_764del, NM_001142502.1) in the PPP1R13L gene, causing a frameshift resulting in a premature termination codon (Pro246GlyfsTer15). The mutation was confirmed by Sanger sequencing and the unaffected parents were shown to be heterozygous for the mutation, which was not found in the gnomAD database.
In a 3-year-old girl of Middle Eastern descent with dilated cardiomyopathy, bifid notched central incisors, and wiry, coarse hair (ARCME; 620519), Henry et al. (2022) identified homozygosity for a 1-bp duplication (c.1068dup, NM_006663.4) in exon 7 of the PPP1R13L gene, causing a frameshift predicted to result in a premature termination codon (Ser357LeufsTer49). Her unaffected first-cousin parents were heterozygous for the mutation, which was not found in the gnomAD database.
In a 2-year-old Iranian boy who was diagnosed with arrhythmogenic cardiomyopathy at age 6 months (ARCME; 620519), Kalayinia et al. (2022) identified homozygosity for a c.580C-T transition (c.580C-T, NM_006663.4) in exon 4 of the PPP1R13L gene, resulting in a gln194-to-ter (Q194X) substitution. He had no hair or skin abnormalities. His first-cousin parents, 2 unaffected sibs, and an unaffected paternal uncle were heterozygous for the mutation, and 2 more unaffected relatives did not carry the mutation. The mutation was not found in the 1000 Genomes Project, gnomAD, Greater Middle East, or Iranome databases.
Bergamaschi, D., Samuels, Y., O'Neil, N. J., Trigiante, G., Crook, T., Hsieh, J.-K., O'Connor, D. J., Zhong, S., Campargue, I., Tomlinson, M. L., Kuwabara, P. E., Lu, X. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nature Genet. 33: 162-167, 2003. [PubMed: 12524540] [Full Text: https://doi.org/10.1038/ng1070]
Bergamaschi, D., Samuels, Y., Sullivan, A., Zvelebil, M., Breyssens, H., Bisso, A., Del Sal, G., Syed, N., Smith, P., Gasco, M., Crook, T., Lu, X. iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72- polymorphic p53. Nature Genet. 38: 1133-1141, 2006. [PubMed: 16964264] [Full Text: https://doi.org/10.1038/ng1879]
Falik-Zaccai, T. C., Barsheshet, Y., Mandel, H., Segev, M., Lorber, A., Gelberg, S., Kalfon, L., Ben Haroush, S., Shalata, A., Gelernter-Yaniv, L., Chaim, S., Raviv Shay, D., and 15 others. Sequence variation in PPP1R13L results in a novel form of cardio-cutaneous syndrome. EMBO Molec. Med. 9: 319-336, 2017. Note: Erratum: EMBO Molec. Med. 9: 1326 only, 2017. [PubMed: 28069640] [Full Text: https://doi.org/10.15252/emmm.201606523]
Gross, M. B. Personal Communication. Baltimore, Md. 2/17/2015.
Henry, A., Bernhardt, I., Hayes, I., Mitchelson, B. Novel PPP1R13L variant expands the phenotype of a rare cardiocutaneous syndrome. Clin. Genet. 102: 461-462, 2022. [PubMed: 35924320] [Full Text: https://doi.org/10.1111/cge.14199]
Herron, B. J., Rao, C., Liu, S., Laprade, L., Richardson, J. A., Olivieri, E., Semsarian, C., Millar, S. E., Stubbs, L., Beier, D. R. A mutation in NFkB interacting protein 1 results in cardiomyopathy and abnormal skin development in wa3 mice. Hum. Molec. Genet. 14: 667-677, 2005. [PubMed: 15661756] [Full Text: https://doi.org/10.1093/hmg/ddi063]
Kalayinia, S., Mahdavi, M., Houshmand, G., Hesami, M., Pourirahim, M., Maleki, M. Novel homozygous stop-gain pathogenic variant of PPP1R13L gene leads to arrhythmogenic cardiomyopathy. BMC Cardiovasc. Disord. 22: 359, 2022. [PubMed: 35933355] [Full Text: https://doi.org/10.1186/s12872-022-02802-7]
Robinson, H. K., Zaklyazminskaya, E., Povolotskaya, I., Surikova, Y., Mallin, L., Armstrong, C., Mabin, D., Benke, P. J., Chrisant, M. R., McDonald, M., Marboe, C. C., Agre, K. E., and 9 others. Biallelic variants in PPP1R13L cause paediatric dilated cardiomyopathy. Clin. Genet. 98: 331-340, 2020. [PubMed: 32666529] [Full Text: https://doi.org/10.1111/cge.13812]
Slee, E. A., Gillotin, S., Bergamaschi, D., Royer, C., Llanos, S., Ali, S., Jin, B., Trigiante, G., Lu, X. The N-terminus of a novel isoform of human iASPP is required for its cytoplasmic localization. Oncogene 23: 9007-9016, 2004. [PubMed: 15489900] [Full Text: https://doi.org/10.1038/sj.onc.1208088]
Yang, J.-P., Hori, M., Sanda, T., Okamoto, T. Identification of a novel inhibitor of nuclear factor-kappa-B, RelA-associated inhibitor. J. Biol. Chem. 274: 15662-15670, 1999. [PubMed: 10336463] [Full Text: https://doi.org/10.1074/jbc.274.22.15662]