Alternative titles; symbols
HGNC Approved Gene Symbol: PSENEN
Cytogenetic location: 19q13.12 Genomic coordinates (GRCh38): 19:35,745,651-35,747,519 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.12 | Acne inversa, familial, 2, with or without Dowling-Degos disease | 613736 | Autosomal dominant | 3 |
PEN2 is a component of the gamma-secretase complex, which also includes presenilin (see PSEN1, 104311) and nicastrin (NCSTN; 605254). The gamma-secretase complex is required for the intramembrane proteolysis of a number of membrane proteins, including the amyloid-beta precursor protein (APP; 104760) and Notch (190198).
Francis et al. (2002) identified 2 presenilin enhancers in C. elegans, Aph1 (see APH1A, 607629) and Pen2. By searching sequence databases, they identified human, mouse, zebrafish, Drosophila, and Arabidopsis homologs of PEN2. The predicted 101-amino acid human PEN2 protein contains 2 transmembrane domains and shares 43% and 96% identity with C. elegans and mouse Pen2, respectively.
Cryoelectron Microscopy
The gamma-secretase complex, comprising presenilin (PSEN1; 104311), PEN2, APH1AL (see 607629), and nicastrin, is a membrane-embedded protease that controls a number of important cellular functions through substrate cleavage. Lu et al. (2014) reported the 3-dimensional structure of an intact human gamma-secretase complex at 4.5-angstrom resolution, determined by cryoelectron microscopy single-particle analysis. The gamma-secretase complex comprises a horseshoe-shaped transmembrane domain, which contains 19 transmembrane segments and a large extracellular domain from nicastrin, which sits immediately above the hollow space formed by the transmembrane horseshoe. The nicastrin extracellular domain is structurally similar to a large family of peptidases exemplified by the glutamate carboxypeptidase PSMA.
By radiation hybrid analysis, Francis et al. (2002) mapped the PEN2 gene to chromosome 19.
Didych et al. (2013) noted that the PSENEN and U2AF1L4 (601080) genes are in a head-to-head orientation on chromosome 19q13.12 with only 157 bp separating their first exons.
By analyzing C. elegans mutant phenotypes, Francis et al. (2002) determined that Aph1 and Pen2 were required for Glp1/Notch-mediated signaling, both in embryonic patterning and in postembryonic germline proliferation. They observed that the human APH1 and PEN2 genes partially rescued the C. elegans mutant phenotypes, demonstrating conserved functions. Human APH1 and PEN2 had to be provided together to rescue the mutant phenotypes, and inclusion of PSEN1 improved rescue. Francis et al. (2002) concluded that APH1 and PEN2 cooperate closely in the same process to promote presenilin activity. Using RNA-mediated interference assays to inactivate Aph1, Pen2, or nicastrin in cultured Drosophila cells, Francis et al. (2002) observed reduction in gamma-secretase cleavage of beta-APP and Notch substrates and reduction in the levels of processed presenilin. They concluded that APH1 and PEN2 are required for Notch pathway signaling, gamma-secretase cleavage of beta-APP, and presenilin protein accumulation. In a commentary, Goutte (2002) discussed the contribution of Francis et al. (2002) to current understanding of how presenilins mediate the gamma-secretase cleavage of Notch transmembrane receptors and transmembrane beta-APP.
Using coimmunoprecipitation experiments, Steiner et al. (2002) showed that PEN2 binds to nicastrin, PSEN1, and PSEN2 (600759), and they concluded that PEN2 is a critical component of PSEN1/gamma-secretase and PSEN2/gamma-secretase complexes. Steiner et al. (2002) observed that Pen2 levels were reduced in mice lacking Psen1 or both Psen1 and Psen2. They also observed that PEN2 levels were reduced upon RNA interference-mediated downregulation of nicastrin. Steiner et al. (2002) concluded that PEN2 expression requires the presence of presenilins and nicastrin. Additionally, they reported that downregulation of PEN2 by RNA interference was associated with reduced presenilin levels, impaired nicastrin maturation, and deficient gamma-secretase complex formation.
Gamma-secretase activity requires the formation of a stable, high molecular mass protein complex that, in addition to the endoproteolyzed fragmented form of presenilin, contains essential cofactors including NCSTN, APH1 (607629, 607630), and PEN2. Takasugi et al. (2003) showed that Drosophila APH1 increases the stability of Drosophila presenilin holoprotein in the complex. Depletion of PEN2 by RNA interference prevented endoproteolysis of presenilin and promoted stabilization of the holoprotein in both Drosophila and mammalian cells, including primary neurons. Coexpression of Drosophila Pen2 with Aph1 and nicastrin increased the formation of presenilin fragments as well as gamma-secretase activity. Thus, Takasugi et al. (2003) concluded that APH1 stabilizes the presenilin holoprotein in the complex, whereas PEN2 is required for endoproteolytic processing of presenilin and conferring gamma-secretase activity to the complex.
Didych et al. (2013) cloned a 269-bp fragment containing the initial parts of the first exons of U2AF1L4 and PSENEN and, using luciferase analysis and fluorescence microscopy, found that both genes were expressed simultaneously. RT-PCR analysis revealed moderate tissue specificity for both genes, although the level of U2AF1L4 may have been underestimated due to the presence of different splice forms. Didych et al. (2013) concluded that the short DNA region between the PSENEN and U2AF1L4 genes behaves as a bidirectional promoter that binds several characteristic transcription factors. They noted that both U2AF1L4 and PSENEN are involved in regulation of T-cell activity.
Wang et al. (2010) identified two 4-generation pedigrees segregating autosomal dominant acne inversa (ACNINV2; 613736). Each family carried a different heterozygous single-basepair substitution leading to haploinsufficiency in affected individuals (607632.0001-607632.0002).
In a mother and daughter with acne inversa, Pink et al. (2011) identified heterozygosity for a 1-bp insertion in the PSENEN gene (607632.0003) that segregated with disease in the family and was not found in controls.
In affected members of 2 unrelated 4-generation Chinese families with acne inversa and Dowling-Degos disease, Zhou et al. (2016) identified heterozygosity for a missense mutation (L65R; 607632.0004) and a splice site mutation (607632.0005), respectively, in the PSENEN gene.
In 10 patients from 6 unrelated families diagnosed with Dowling-Degos disease, of whom all were negative for mutation in DDD-associated genes and 6 also exhibited acne inversa, Ralser et al. (2017) performed exome sequencing and identified heterozygous mutations in the PSENEN gene (see, e.g., 607632.0006 and 607632.0007). Noting that all 6 patients with acne inversa reported nicotine use and/or obesity, the authors hypothesized that PSENEN mutation carriers present primarily with DDD, whereas those with a history of nicotine use or obesity have an increased susceptibility to comorbid acne inversa.
Li et al. (2017) reviewed 11 previously reported families (Wang et al., 2010; Pink et al., 2011; Zhou et al., 2016; Ralser et al., 2017) and 1 unpublished Chinese family with PSENEN-associated acne inversa and/or DDD, and also reported an additional large 4-generation Chinese pedigree (family 5) with acne inversa and the L65R mutation (607632.0004) in the PSENEN gene. Li et al. (2017) observed intrafamilial variability in severity of lesions, which they suggested might be due to reduced penetrance involving different genetic and environmental factors. Noting that more than half of the patients from the 13 families showed only acne inversa and a minority showed acne inversa with comorbid DDD, the authors proposed that the comanifestation of acne inversa and DDD represents a subtype of acne inversa in some PSENEN mutation carriers.
By screening a library of about 80,000 chemical compounds, Kounnas et al. (2010) identified a class of gamma-secretase modulators (GSMs), diarylaminothiazoles, or series A GSMs, that could target production of the fibrillogenic peptides amyloid (A)-beta-42 and A-beta-40 (see 104760) in cell lines and in Tg 2576 transgenic Alzheimer disease (AD; 104300) mice. Immobilized series A GSMs bound to Pen2 and, to a lesser degree, Psen1. Series A GSMs reduced gamma-secretase activity without interfering with related off-target reactions, lowered A-beta-42 levels in both plasma and brain of Tg 2576 mice, and reduced plaque density and amyloid in Tg 2576 hippocampus and cortex. Daily dosing was well tolerated over the 7-month study.
Ralser et al. (2017) performed mopholino knockdown of psenen in zebrafish and observed a major decrease in pigment cells in morphant larvae compared to controls. In addition, the knockdown zebrafish larvae showed substantial alterations in distribution of pigmentation, especially in the facial and tail regions, making them easily distinguishable from controls. The morphants also displayed significantly fewer pigment cells in the dorsal area of the head, whereas hyperpigmentation of the tail fins was present. The authors considered the pigmentation abnormalities to be the phenotypic counterpart to human Dowling-Degos disease. In vivo monitoring of pigment cells in developing zebrafish larvae showed organized, target-oriented migration in controls, resulting in the typical larval stripe pattern, whereas morphant pigment cells exhibited disordered and meandering migration. All the pigment cells in the controls were regular in size and showed similar flat and elongated morphology, whereas morphant pigment cells were irregular in size. Ralser et al. (2017) suggested that the underlying pathogenesis of DDD involves disordered migration of melanocytic precursor cells into the epidermis, with irregular differentiation of epidermal melanocytes.
In a 4-generation Han Chinese family segregating autosomal dominant acne inversa (ACNINV2; 613736), Wang et al. (2010) identified a single-basepair deletion of a guanine in the PSENEN gene (c.66delG) resulting in frameshift and a premature termination codon (Phe23LeufsTer46). This mutation was not identified in chromosomes from 200 ethnically matched control individuals. Li et al. (2017) reexamined affected individuals in this family and observed manifestations of Dowling-Degos disease in 4 of the 11 patients.
In a 4-generation Han Chinese family segregating autosomal dominant acne inversa (ACNINV2; 613736), Wang et al. (2010) identified a single-basepair deletion at nucleotide 279 of the PSENEN gene (c.279delC), resulting in a frameshift and delayed termination codon (Phe94SerfsTer51). This mutation was not detected in chromosomes from 200 ethnically matched control individuals.
In a mother and daughter with acne inversa (ACNINV2; 613736), Pink et al. (2011) identified heterozygosity for a 1-bp insertion (c.66_67insG) in the PSENEN gene, causing a frameshift predicted to result in a premature termination codon (Phe23ValfsTer98). The mutation was not found in the unaffected father or sister, or in 200 control chromosomes of European ancestry. RT-PCR of mRNA from patient lymphoblasts showed a marked reduction in PSENEN expression compared to controls, suggesting that the mutant transcript is subject to nonsense-mediated decay.
In affected members of a 4-generation Chinese family (family 1) with acne inversa and Dowling-Degos disease (ACNINV2; 613736), Zhou et al. (2016) identified heterozygosity for a c.194T-G transversion in the PSENEN gene, resulting in a leu65-to-arg (L65R) substitution within the second transmembrane domain. The mutation segregated with disease in the family and was not found in 100 ethnically matched controls. One patient in this family developed metastatic squamous cell carcinoma of the anal canal.
In a large 4-generation Chinese family (family 5) with acne inversa, Li et al. (2017) identified heterozygosity for the L65R mutation, which segregated with disease. Of 21 affected family members, 1 also exhibited the typical reticulated pigmentation of Dowling-Degos disease, whereas 2 other patients showed macular lesions on the nape of the neck.
In affected members of a 4-generation Chinese family (family 2) with acne inversa and Dowling-Degos disease (ACNINV2; 613736), Zhou et al. (2016) identified heterozygosity for a splice site mutation (c.167-2A-G) in intron 3 of the PSENEN gene. The mutation segregated with disease in the family and was not found in 100 ethnically matched controls.
In a German father and daughter with acne inversa (ACNINV2; 613736), Ralser et al. (2017) identified heterozygosity for a c.35T-A transversion in exon 2 of the PSENEN gene, resulting in a leu12-to-ter (L12X) substitution. The mutation segregated with disease in the family and was not found in the dbSNP (build 137), 1000 Genomes Project, Exome Variant Server, or ExAC databases. The father also exhibited Dowling-Degos disease (DDD) on histology; information regarding DDD was not available for the daughter.
In affected members of a 4-generation Indian family with acne inversa with Dowling-Degos disease (ACNINV2; 613736), Ralser et al. (2017) identified heterozygosity for a splice site mutation (c.62-1G-C) in intron 2 of the PSENEN gene. Exon trapping revealed complete skipping of exon 2, resulting in an in-frame deletion of 35 amino acids within the cytoplasmic domain. The mutation segregated with disease in the family and was not found in the dbSNP (build 137), 1000 Genomes Project, Exome Variant Server, or ExAC databases. Of the 3 patients for whom clinical information was reported, 2 showed Dowling-Degos disease (DDD) as well as acne inversa and both were obese, whereas the third patient, who was not obese, showed only features of DDD.
Didych, D. A., Shamsutdinov, M. F., Smirnov, N. A., Akopov, S. B., Monastyrskaya, G. S., Uspenskaya, N. Y., Nikolaev, L. G., Sverdlov, E. D. Human PSENEN and U2AF1L4 genes are concertedly regulated by a genuine bidirectional promoter. Gene 515: 34-41, 2013. [PubMed: 23246698] [Full Text: https://doi.org/10.1016/j.gene.2012.11.058]
Francis, R., McGrath, G., Zhang, J., Ruddy, D. A., Sym, M., Apfeld, J., Nicoll, M., Maxwell, M., Hai, B., Ellis, M. C., Parks, A. L., Xu, W., Li, J., Gurney, M., Myers, R. L., Himes, C. S., Hiebsch, R., Ruble, C., Nye, J. S., Curtis, D. aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of beta-APP, and presenilin protein accumulation. Dev. Cell 3: 85-97, 2002. [PubMed: 12110170] [Full Text: https://doi.org/10.1016/s1534-5807(02)00189-2]
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Kounnas, M. Z., Danks, A. M., Cheng, S., Tyree, C., Ackerman, E., Zhang, X., Ahn, K., Nguyen, P., Comer, D., Mao, L., Yu, C., Pleynet, D., and 9 others. Modulation of gamma-secretase reduces beta-amyloid deposition in a transgenic mouse model of Alzheimer's disease. Neuron 67: 769-780, 2010. [PubMed: 20826309] [Full Text: https://doi.org/10.1016/j.neuron.2010.08.018]
Li, C., Li, W., Xu, H., Zhang, X., Su, B., Zhang, W., Zhang, X., Wang, B. PSENEN mutation carriers with co-manifestation of acne inversa (AI) and Dowling-Degos disease (DDD): is AI or DDD the subphenotype? (Letter) J. Invest. Derm. 137: 2234-2236, 2017. [PubMed: 28601418] [Full Text: https://doi.org/10.1016/j.jid.2017.05.021]
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Pink, A. E., Simpson, M. A., Brice, G. W., Smith, C. H., Desai, N., Mortimer, P. S., Barker, J. N. W. N., Trembath, R. C. PSENEN and NCSTN mutations in familial hidradenitis suppurativa (acne inversa). (Letter) J. Invest. Derm. 131: 1568-1570, 2011. [PubMed: 21412258] [Full Text: https://doi.org/10.1038/jid.2011.42]
Ralser, D. J., Basmanav, F. B. U., Tafazzoli, A., Wititsuwannakul, J., Delker, S., Danda, S., Thiele, H., Wolf, S., Busch, M., Pulimood, S. A., Altmuller, J., Nurnberg, P., Lacombe, D., Hillen, U., Wenzel, J., Frank, J., Odermatt, B., Betz, R. C. Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa. J. Clin. Invest. 127: 1485-1490, 2017. [PubMed: 28287404] [Full Text: https://doi.org/10.1172/JCI90667]
Steiner, H., Winkler, E., Edbauer, D., Prokop, S., Basset, G., Yamasaki, A., Kostka, M., Haass, C. PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin. J. Biol. Chem. 277: 39062-39065, 2002. [PubMed: 12198112] [Full Text: https://doi.org/10.1074/jbc.C200469200]
Takasugi, N., Tomita, T., Hayashi, I., Tsuruoka, M., Niimura, M., Takahashi, Y., Thinakaran, G., Iwatsubo, T. The role of presenilin cofactors in the gamma-secretase complex. Nature 422: 438-441, 2003. [PubMed: 12660785] [Full Text: https://doi.org/10.1038/nature01506]
Wang, B., Yang, W., Wen, W., Sun, J., Su, B., Liu, B., Ma, D., Lv, D., Wen, Y., Qu, T., Chen, M., Sun, M., Shen, Y., Zhang, X. Gamma-secretase gene mutations in familial acne inversa. Science 330: 1065 only, 2010. [PubMed: 20929727] [Full Text: https://doi.org/10.1126/science.1196284]
Zhou, C., Wen, G.-D., Soe, L. M., Xu, H.-J., Du, J., Zhang, J.-Z. Novel mutations in PSENEN gene in two Chinese acne inversa families manifested as familial multiple comedones and Dowling-Degos disease. Chinese Med. J. 129: 2834-2839, 2016. [PubMed: 27900998] [Full Text: https://doi.org/10.4103/0366-6999.194648]