PSENEN Mutation Carriers with Co-manifestation of Acne Inversa (AI) and Dowling-Degos Disease (DDD): Is AI or DDD the Subphenotype?
2017; Elsevier BV; Volume: 137; Issue: 10 Linguagem: Inglês
10.1016/j.jid.2017.05.021
ISSN1523-1747
AutoresChengrang Li, Wenrui Li, Haoxiang Xu, Xiaofeng Zhang, Bin Su, Wanlu Zhang, Xue Zhang, Baoxi Wang,
Tópico(s)NF-κB Signaling Pathways
ResumoRalser et al.'s study, published in the Journal of Clinical Investigation in March 2017, is very interesting (Ralser et al., 2017Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al.Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (60) Google Scholar). The authors present important evidence demonstrating that most deleterious presenilin enhancer-2 (PSENEN, NM_172341.3) mutation carriers present primarily with Dowling-Degos disease (DDD), and patients with a history of nicotine abuse or obesity have an increased susceptibility to comorbid acne inversa (AI). Moreover, among PSENEN mutation carriers, the DDD subphenotype is associated with increased susceptibility to AI. However, these results should be interpreted carefully. Here, we reviewed previously reported AI and DDD cases (families 1–13, including our unpublished pedigree, all subjects provided full written consents, and the study was conducted in accordance with the Declaration of Helsinki principle and approved by the Ethics Committee of the Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College) with PSENEN mutations (Table 1 and Supplementary Figure S1 online; the tables and figures include family pedigree maps that refer to the Supplementary Materials and Methods online). In 2010, Wang et al. identified mutations in PSENEN, nicastrin (NM_015331.2), and presenilin-1 (NM_000021.3)—which encode three of the four proteins of γ-secretase—to be responsible for familial AI in six Chinese families (Wang et al., 2010Wang B. Yang W. Wen W. Sun J. Su B. Liu B. et al.Gamma-secretase gene mutations in familial acne inversa.Science. 2010; 330: 1065Crossref PubMed Scopus (307) Google Scholar). Pink et al., 2011Pink A.E. Simpson M.A. Brice G.W. Smith C.H. Desai N. Mortimer P.S. et al.PSENEN and NCSTN mutations in familial hidradenitis suppurativa (acne inversa).J Invest Dermatol. 2011; 131: 1568-1570Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar reported patients with AI with PSENEN mutations and hyperpigmentation (family 1) (Pink et al., 2011Pink A.E. Simpson M.A. Brice G.W. Smith C.H. Desai N. Mortimer P.S. et al.PSENEN and NCSTN mutations in familial hidradenitis suppurativa (acne inversa).J Invest Dermatol. 2011; 131: 1568-1570Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar). Zhou et al., 2016Zhou 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.Chin Med J. 2016; 129: 2834-2839Crossref PubMed Scopus (28) Google Scholar reported co-manifestation of DDD and AI in individuals (families 6 and 7) with PSENEN mutations (Zhou et al., 2016Zhou 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.Chin Med J. 2016; 129: 2834-2839Crossref PubMed Scopus (28) Google Scholar). Detailed descriptions are presented in the Supplementary Materials and Methods.Table 1Families with PSENEN mutations in our reviewFamilyEthnicityPSENEN mutationGenerationTotal individuals (including patients and normal)Number of patients with PSENEN mutation in different phenotypesReferenceAIDDDCo-manifestation1Britishc.66_67insG37002 (II:2, III:1with light macular hyperpigmentation)Pink et al., 2011Pink A.E. Simpson M.A. Brice G.W. Smith C.H. Desai N. Mortimer P.S. et al.PSENEN and NCSTN mutations in familial hidradenitis suppurativa (acne inversa).J Invest Dermatol. 2011; 131: 1568-1570Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar2Chinesec.66delG440704 (II:2, III:6, III:8, III:12)Wang et al., 2010Wang B. Yang W. Wen W. Sun J. Su B. Liu B. et al.Gamma-secretase gene mutations in familial acne inversa.Science. 2010; 330: 1065Crossref PubMed Scopus (307) Google Scholar3Chinesec.279delC4481900Wang et al., 2010Wang B. Yang W. Wen W. Sun J. Su B. Liu B. et al.Gamma-secretase gene mutations in familial acne inversa.Science. 2010; 330: 1065Crossref PubMed Scopus (307) Google Scholar4Chinesec.229_230insCACC4301002 (II:7, III:1with marked variability in severity of hyperpigmentation)Zhang et al. (unpublished data)5Chinesec.194T>G p.L65R4601803 (II:7 with DDD-like symptom and II:3, II:5 with macular pigmentation)Our new pedigree, 2017 (see Supplementary Table S3 online)6Chinesec.194T>G417Few of the 12 affected individuals0Most of the 12 affected individualsZhou et al., 2016Zhou 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.Chin Med J. 2016; 129: 2834-2839Crossref PubMed Scopus (28) Google Scholar7Chinesec.167-2A>G431Few of the 12 affected individuals0Most of the 12 affected individualsZhou et al., 2016Zhou 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.Chin Med J. 2016; 129: 2834-2839Crossref PubMed Scopus (28) Google Scholar8Germanc.216delCNANA010Ralser et al., 2017Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al.Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (60) Google Scholar9Germanc.115C>TNANA001Ralser et al., 2017Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al.Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (60) Google Scholar10Indianc.62-1G>C419012Ralser et al., 2017Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al.Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (60) Google Scholar11Thailand84_85insT318020Ralser et al., 2017Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al.Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (60) Google Scholar12Germanc.35T>A23101Ralser et al., 2017Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al.Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (60) Google Scholar13Frenchg.1412T>CNANA001Ralser et al., 2017Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al.Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (60) Google ScholarAbbreviations: AI, acne inversa; DDD, Dowling-Degos disease; F, female; M, male; NA, clinical information was not available; PSENEN, presenilin enhancer-2. Open table in a new tab Abbreviations: AI, acne inversa; DDD, Dowling-Degos disease; F, female; M, male; NA, clinical information was not available; PSENEN, presenilin enhancer-2. Ralser et al., 2017Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al.Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (60) Google Scholar described the clinical presentation of 10 patients with PSENEN mutations in 6 different families (i.e., 6 probands) (families 8–13) as well as the pedigree maps of 3 families (families 10–12). More than half the patients (including 5 AI-DDD, 1 AI, and 4 DDD) exhibited clinical features of AI. Thus, the review of the families mentioned above (families 1–13) suggested that PSENEN mutation carriers display three different phenotypes: AI alone (highest), DDD alone (lowest), and AI-DDD co-manifestation (Table 1 and Supplementary Table S1 online). However, Ralser et al., 2017Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al.Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (60) Google Scholar are unclear as to why patients with DDD with PSENEN gene mutations are histopathologically characterized by follicular hyperkeratosis. We found that elderly patients in family 5 had follicular papules, comedones, noninflammatory nodules, and scattered atrophic scars on their axillae, perianal area, and nape of the neck (Supplementary Figure S2Ca–f and Supplementary Table S3 online). These findings may not completely meet the diagnostic criteria for AI (Revuz and Jemec, 2016Revuz J.E. Jemec G.B. Diagnosing hidradenitis suppurativa.Dermatol Clin. 2016; 34: 1-5Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar, Zouboulis et al., 2015Zouboulis C.C. Del Marmol V. Mrowietz U. Prens E.P. Tzellos T. Jemec G.B. Hidradenitis suppurativa/acne inversa: criteria for diagnosis, severity assessment, classification and disease evaluation.Dermatology. 2015; 231: 184-190Crossref PubMed Scopus (204) Google Scholar). Moreover, the skin lesions showed variable severity in patients with AI in families 2, 3, and 4, all of whom also had family histories of AI and γ-secretase gene mutations. Thus, we hypothesize that the variable severity may be caused by reduced penetrance, owing to the combination of different genetic and environmental factors (Cooper et al., 2013Cooper D.N. Krawczak M. Polychronakos C. Tyler-Smith C. Kehrer-Sawatzki H. Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease.Hum Genet. 2013; 132: 1077-1130Crossref PubMed Scopus (396) Google Scholar). Some PSENEN mutation carriers with mild AI manifestations are likely to be misdiagnosed because the acknowledged diagnostic criteria for AI might be too strict for pathogenic gene carriers. Ralser et al., 2017Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al.Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (60) Google Scholar also performed exome sequencing in six patients in the Indian family but provided the clinical features for only three patients (Ralser et al., 2017Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al.Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (60) Google Scholar). Careful physical examination is needed to detect mild lesions such as folliculitis, comedones, and atrophic scars, which may avoid the omission of some potential patients with AI. Moreover, a detailed family survey will help understand the phenotype. Furthermore, Ralser et al., 2017Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al.Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (60) Google Scholar excluded patients with mutations in keratin 5 (NM_000424.3) (Betz et al., 2006Betz R.C. Planko L. Eigelshoven S. Hanneken S. Pasternack S.M. Bussow H. et al.Loss-of-function mutations in the keratin 5 gene lead to Dowling-Degos disease.Am J Hum Genet. 2006; 78: 510-519Abstract Full Text Full Text PDF PubMed Scopus (199) Google Scholar), protein O-fucosyltransferase 1 (NM_015352.1) (Li et al., 2013Li M. Cheng R. Liang J. Yan H. Zhang H. Yang L. et al.Mutations in POFUT1, encoding protein O-fucosyltransferase 1, cause generalized Dowling-Degos disease.Am J Hum Genet. 2013; 92: 895-903Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar), or protein O-glucosyltransferase 1 (POGLUT1, NM_152305.2) (Basmanav et al., 2014Basmanav F.B. Oprisoreanu A.M. Pasternack S.M. Thiele H. Fritz G. Wenzel J. et al.Mutations in POGLUT1, encoding protein O-glucosyltransferase 1, cause autosomal-dominant Dowling-Degos disease.Am J Hum Genet. 2014; 94: 135-143Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar), all of which are pathogenic genes for DDD (Ralser et al., 2017Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al.Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (60) Google Scholar). But mutations in the other two known AI genes namely nicastrin and presenilin-1 have not been mentioned (Supplementary Table S4 online). Disturbances in melanocyte migration and differentiation in PSENEN- or protein O-fucosyltransferase 1-knockdown zebrafish models parallel those of cutaneous lesions in patients with DDD (Li et al., 2013Li M. Cheng R. Liang J. Yan H. Zhang H. Yang L. et al.Mutations in POFUT1, encoding protein O-fucosyltransferase 1, cause generalized Dowling-Degos disease.Am J Hum Genet. 2013; 92: 895-903Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar, Ralser et al., 2017Ralser D.J. Basmanav F.B. Tafazzoli A. Wititsuwannakul J. Delker S. Danda S. et al.Mutations in gamma-secretase subunit-encoding PSENEN underlie Dowling-Degos disease associated with acne inversa.J Clin Invest. 2017; 127: 1485-1490Crossref PubMed Scopus (60) Google Scholar). These findings are important for pathogenic hypotheses linking mutations to the clinical manifestations of DDD. Although approximately 70% of human genes have at least one obvious zebrafish ortholog (Howe et al., 2013Howe K. Clark M.D. Torroja C.F. Torrance J. Berthelot C. Muffato M. et al.The zebrafish reference genome sequence and its relationship to the human genome.Nature. 2013; 496: 498-503Crossref PubMed Scopus (2779) Google Scholar), substantial histological and immunological differences exist between zebrafish models and in vivo human disease. Moreover, zebrafish cannot be used as animal models for inflammatory hair follicle disorders. Therefore, we tend to speculate that the clinical features of zebrafish with PSENEN knockdown may be consistent with the hyperpigmentation found in some patients with AI with PSENEN mutations. Interestingly, only a minority of patients with AI with PSENEN mutations show comorbid DDD. Moreover, mutations of protein O-fucosyltransferase 1 and POGLUT1, which encode upstream components of γ-secretase in the Notch signaling pathway, are associated with DDD. The pathogenic mechanisms in the two diseases appear to involve disturbed Notch signaling due to impaired γ-secretase function in familial AI and posttranslational modifications of Notch proteins in patients with DDD with protein O-fucosyltransferase 1 or POGLUT1 mutations. These findings suggest that PSENEN mutations promote the occurrence and development of AI and increase the susceptibility to comorbid DDD via disrupted Notch signaling. Reticulate acropigmentation of Kitamura, an autosomal-dominant disorder with clinical and histopathological manifestations similar to DDD, differs in the involvement of acral areas. Metalloprotease domain-containing protein 10 (NM_001110.3), which occurs between POGLUT1 and γ-secretase in the Notch signaling pathway, could influence Notch signaling by impairing ectodomain shedding of Notch proteins. Mutations in metalloprotease domain-containing protein 10, which encodes a zinc metalloprotease, cause reticulate acropigmentation of Kitamura (Kono et al., 2013Kono M. Sugiura K. Suganuma M. Hayashi M. Takama H. Suzuki T. et al.Whole-exome sequencing identifies ADAM10 mutations as a cause of reticulate acropigmentation of Kitamura, a clinical entity distinct from Dowling-Degos disease.Hum Mol Genet. 2013; 22: 3524-3533Crossref PubMed Scopus (30) Google Scholar). Given that the abnormal skin pigmentation and histologic presentation in DDD, reticulate acropigmentation of Kitamura, and some patients with AI are similar, we speculate that mutations of genes between sites encoded by the DDD and AI pathogenic genes in the Notch signaling pathway may lead to pigmentation disorders characterized by varying degrees of penetrance and hyperpigmentation. These patients may show phenotypes ranging from brown macules to reticulate hyperpigmentation. The results of histologic analyses may show filiform epithelial downgrowth of epidermal rete ridges with a concentration of melanin at the tips. In summary, we hypothesize that the co-manifestation of AI and DDD is a subtype of AI in some PSENEN mutation carriers. We predict that genes existing between POGLUT1 and γ-secretase, other than metalloprotease domain-containing protein 10, might be responsible for varying degrees of pigmentation. Nicastrin, presenilin-1, and PSENEN mutations have been reported in patients with AI. However, no report has described nicastrin or presenilin-1 mutations in charge of pigmentation. Additional clinical reports and studies of AI and DDD are necessary to clarify the association between them and to identify the contributions of genetic and environmental factors to these conditions. The authors state no conflict of interest. We thank Qi Li for helping search the literature. This study was funded by the National Natural Science Foundation of China (grant numbers 81472872 and 81472905) and CAMS Innovation Fund for Medical Sciences (grant numbers 2016-I2M-1-002 and 2016-I2M-1-003). Download .pdf (3.32 MB) Help with pdf files Supplementary Data
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