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Hailey–Hailey disease from a clinical perspective
Cell Calcium 43 (2008) 105–106
Comment
Hailey–Hailey disease from a clinical perspective To the Editor, We are living the era of translational research in biological sciences. Consequently, molecular biologists are under pressure to directly relate their basic scientific work to clinical aspects of human disease. This can frequently lead to conflicts that may arise from the deterministic interpretation of Mendel’s, Darwin’s and Watson-Crick’s work. As Strohman phrases it: “. . .the Watson-Crick era, which began as a narrowly defined and proper theory and paradigm of the gene has mistakenly evolved into a theory and a paradigm of life: That is, into a revived and thoroughly molecular form of genetic determinism.” However, the failure of this paradigm resides “. . .in the mistaken idea that complex behavior may be traced solely to genetic agents and their surrogate proteins without recourse to the properties originating from the complex and nonlinear interactions of those genes” ([1] first two paragraphs). This conflict is certainly present in the recent review of Missiaen et al.: “Calcium in the Golgi apparatus” [2]. Being a leading group in this field, they provide an excellent, comprehensive summary about the molecular biology and genetics of the secretory-pathway Ca2+ -ATPases (SPCAs). Despite of the title they take the review further and discuss not only the molecular properties of SPCAs and SPCA1 specifically, but also the genetics and pathophysiology of Hailey–Hailey disease (HHD), which has been linked to mutations in ATP2C1, encoding SPCA1. This approach naturally suggests that molecular studies on SPCA1 may bring us closer to understanding HHD pathophysiology. However, from a clinical perspective HHD is a typical example of a dominantly inherited disease that keeps medical geneticists perplexed by the significantly variable expressivity of a genetic defect [3]. For this reason, the authors are wisely cautious with their interpretations of the molecular and cellular studies in regards of HHD on one hand. On the other hand, it is also a mistake to be so cautious and to avoid final conclusions about HHD pathogenesis. It is cited in the review that: “there is no correlation between the nature of the mutation and the clinical features, like age of onset, pattern of outbreak, severity, or disease 0143-4160/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ceca.2007.06.005
progression” and, “. . . the phenotype is strongly influenced by genetic modifiers and/or environmental factors” (3.1, first paragraph). It is also mentioned that: “the loss of one functional ATP2C1 allele on its own is not sufficient to cause the HHD symptoms. Indeed, the skin of HHD patients is typically symptom-free during the first decades of life and even thereafter the symptoms are only seen in certain areas of the skin in response to external noxious stimuli” (3.4, last paragraph). Additionally, Missiaen et al. note that “the symptoms in HHD patients can be elicited in a matter of minutes by locally rubbing the skin” (3.4, last paragraph). Yet, they fail to highlight that based on these clinical facts the key feature of HHD pathophysiology is the alteration in epidermal defensive mechanisms at the organ level, which alteration is irrespective of the specific genetic defect in SPCA1 [4–6]. Furthermore, desmosome formation and response to UVB irradiation are similar in HHD and normal keratinocyte monolayers [7]. These findings also support that disturbances of molecular interactions resulting from dominant ATP2C1 mutations directly at the intracellular, cellular level are physiologically minor. Rather, the already emphasized alteration in the calcium homeostasis of the epidermis as an organ, that results from ATP2C1 mutations is likely a/the key component in the pathogenesis of HHD [5]. However, the authors of the criticized review are hesitant to acknowledge or dispute these conclusions. They only make a weak statement that “clearly, other external factors contribute to the development of the phenotype” (3.4, last paragraph) and stress that the role of SPCA pumps in cellular ion homeostasis seems to be crucial for normal cell physiology, since mutations in SPCA1 cause HHD (conclusions). Their conflict likely roots from the hesitation to admit that as a consequence of the described clinical and experimental data, molecular and cellular observations bare limited value in understanding HHD pathophysiology and do not provide any guidance currently in the prognosis of patients affected by the disorder [4]. Additionally, the earlier mentioned deterministic interpretation of the gene paradigm that infiltrates our biologic thought process likely contributes to the controversies. Nonetheless, this does not decrease the significance of basic molecular/cellular observations in regards of SPCAs, just places them in a different context. For example, understanding the direct and indirect molecular and cellular consequences of ATP2C1 mutations
106
Comment / Cell Calcium 43 (2008) 105–106
may promote the development of further therapeutic modalities for HHD [8,9] and can point to yet unexplored aspects of the disease [10]. On the contrary to the authors (see conclusions), I believe that we are beginning to understand how much we still do not understand about SPCA1 physiology. The urge to interpret basic research directly into translational is not necessarily fruitful and may lead to mis-/over-interpretation of otherwise significant results. Therefore, unwanted pressures of translational research should be alleviated at the basic scientific level. It is our role to convey this properly to the public that expects rapid solutions for genetic disorders since the completion of the human genome project.
References [1] R.C. Strohman, The coming Kuhnian revolution in biology, Nat. Biotechnol. 15 (1997) 194–200. [2] L. Missiaen, L. Dode, J. Vanoevelen, et al., Calcium in the Golgi apparatus, Cell Calcium 41 (2007) 405–416. [3] R. Kellermayer, Physiologic noise obscures genotype–phenotype correlations, Am. J. Med. Genet. A. 143 (2007) 1306–1307. [4] R. Szigeti, R. Kellermayer, Autosomal-dominant calcium ATPase disorders, J. Invest. Dermatol. 126 (2006) 2370–2376. [5] R. Kellermayer, Hailey–Hailey disease as an orthodisease of PMR1 deficiency in Saccharomyces cerevisiae, FEBS Lett. 579 (2005) 221–225.
[6] R. Szigeti, S.C. Chao, O. Szasz, et al., Premenstrual exacerbation in calcium ATPase disorders of the skin, J. Eur. Acad. Dermatol. Venereol. 21 (2007) 412–413. [7] M. Bernards, B.P. Korge, Desmosome assembly and keratin network formation after Ca2+/serum induction and UVB radiation in Hailey–Hailey keratinocytes, J. Invest. Dermatol. 114 (2000) 1058–1061. [8] R. Szigeti, R. Kellermayer, Hailey–Hailey disease and calcium: lessons from yeast, J. Invest. Dermatol. 123 (2004) 1195–1196. [9] R. Kellermayer, R. Szigeti, K.M. Keeling, et al., Aminoglycosides as potential pharmacogenetic agents in the treatment of Hailey–Hailey disease, J. Invest. Dermatol. 126 (2006) 229–231. [10] R. Szigeti, A. Miseta, R. Kellermayer, Calcium and magnesium competitively influence the growth of a PMR1 deficient Saccharomyces cerevisiae strain, FEMS Microbiol. Lett. 251 (2005) 333–339.
Richard Kellermayer ∗ Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, 6621 Fannin Street, CC1010.00, Houston, TX 77030-2399, USA ∗ Tel.:
+1 832 822 3131; fax: +1 832 825 3633. E-mail address: [email protected] 30 April 2007 Available online 17 August 2007
Comment
Hailey–Hailey disease from a clinical perspective To the Editor, We are living the era of translational research in biological sciences. Consequently, molecular biologists are under pressure to directly relate their basic scientific work to clinical aspects of human disease. This can frequently lead to conflicts that may arise from the deterministic interpretation of Mendel’s, Darwin’s and Watson-Crick’s work. As Strohman phrases it: “. . .the Watson-Crick era, which began as a narrowly defined and proper theory and paradigm of the gene has mistakenly evolved into a theory and a paradigm of life: That is, into a revived and thoroughly molecular form of genetic determinism.” However, the failure of this paradigm resides “. . .in the mistaken idea that complex behavior may be traced solely to genetic agents and their surrogate proteins without recourse to the properties originating from the complex and nonlinear interactions of those genes” ([1] first two paragraphs). This conflict is certainly present in the recent review of Missiaen et al.: “Calcium in the Golgi apparatus” [2]. Being a leading group in this field, they provide an excellent, comprehensive summary about the molecular biology and genetics of the secretory-pathway Ca2+ -ATPases (SPCAs). Despite of the title they take the review further and discuss not only the molecular properties of SPCAs and SPCA1 specifically, but also the genetics and pathophysiology of Hailey–Hailey disease (HHD), which has been linked to mutations in ATP2C1, encoding SPCA1. This approach naturally suggests that molecular studies on SPCA1 may bring us closer to understanding HHD pathophysiology. However, from a clinical perspective HHD is a typical example of a dominantly inherited disease that keeps medical geneticists perplexed by the significantly variable expressivity of a genetic defect [3]. For this reason, the authors are wisely cautious with their interpretations of the molecular and cellular studies in regards of HHD on one hand. On the other hand, it is also a mistake to be so cautious and to avoid final conclusions about HHD pathogenesis. It is cited in the review that: “there is no correlation between the nature of the mutation and the clinical features, like age of onset, pattern of outbreak, severity, or disease 0143-4160/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.ceca.2007.06.005
progression” and, “. . . the phenotype is strongly influenced by genetic modifiers and/or environmental factors” (3.1, first paragraph). It is also mentioned that: “the loss of one functional ATP2C1 allele on its own is not sufficient to cause the HHD symptoms. Indeed, the skin of HHD patients is typically symptom-free during the first decades of life and even thereafter the symptoms are only seen in certain areas of the skin in response to external noxious stimuli” (3.4, last paragraph). Additionally, Missiaen et al. note that “the symptoms in HHD patients can be elicited in a matter of minutes by locally rubbing the skin” (3.4, last paragraph). Yet, they fail to highlight that based on these clinical facts the key feature of HHD pathophysiology is the alteration in epidermal defensive mechanisms at the organ level, which alteration is irrespective of the specific genetic defect in SPCA1 [4–6]. Furthermore, desmosome formation and response to UVB irradiation are similar in HHD and normal keratinocyte monolayers [7]. These findings also support that disturbances of molecular interactions resulting from dominant ATP2C1 mutations directly at the intracellular, cellular level are physiologically minor. Rather, the already emphasized alteration in the calcium homeostasis of the epidermis as an organ, that results from ATP2C1 mutations is likely a/the key component in the pathogenesis of HHD [5]. However, the authors of the criticized review are hesitant to acknowledge or dispute these conclusions. They only make a weak statement that “clearly, other external factors contribute to the development of the phenotype” (3.4, last paragraph) and stress that the role of SPCA pumps in cellular ion homeostasis seems to be crucial for normal cell physiology, since mutations in SPCA1 cause HHD (conclusions). Their conflict likely roots from the hesitation to admit that as a consequence of the described clinical and experimental data, molecular and cellular observations bare limited value in understanding HHD pathophysiology and do not provide any guidance currently in the prognosis of patients affected by the disorder [4]. Additionally, the earlier mentioned deterministic interpretation of the gene paradigm that infiltrates our biologic thought process likely contributes to the controversies. Nonetheless, this does not decrease the significance of basic molecular/cellular observations in regards of SPCAs, just places them in a different context. For example, understanding the direct and indirect molecular and cellular consequences of ATP2C1 mutations
106
Comment / Cell Calcium 43 (2008) 105–106
may promote the development of further therapeutic modalities for HHD [8,9] and can point to yet unexplored aspects of the disease [10]. On the contrary to the authors (see conclusions), I believe that we are beginning to understand how much we still do not understand about SPCA1 physiology. The urge to interpret basic research directly into translational is not necessarily fruitful and may lead to mis-/over-interpretation of otherwise significant results. Therefore, unwanted pressures of translational research should be alleviated at the basic scientific level. It is our role to convey this properly to the public that expects rapid solutions for genetic disorders since the completion of the human genome project.
References [1] R.C. Strohman, The coming Kuhnian revolution in biology, Nat. Biotechnol. 15 (1997) 194–200. [2] L. Missiaen, L. Dode, J. Vanoevelen, et al., Calcium in the Golgi apparatus, Cell Calcium 41 (2007) 405–416. [3] R. Kellermayer, Physiologic noise obscures genotype–phenotype correlations, Am. J. Med. Genet. A. 143 (2007) 1306–1307. [4] R. Szigeti, R. Kellermayer, Autosomal-dominant calcium ATPase disorders, J. Invest. Dermatol. 126 (2006) 2370–2376. [5] R. Kellermayer, Hailey–Hailey disease as an orthodisease of PMR1 deficiency in Saccharomyces cerevisiae, FEBS Lett. 579 (2005) 221–225.
[6] R. Szigeti, S.C. Chao, O. Szasz, et al., Premenstrual exacerbation in calcium ATPase disorders of the skin, J. Eur. Acad. Dermatol. Venereol. 21 (2007) 412–413. [7] M. Bernards, B.P. Korge, Desmosome assembly and keratin network formation after Ca2+/serum induction and UVB radiation in Hailey–Hailey keratinocytes, J. Invest. Dermatol. 114 (2000) 1058–1061. [8] R. Szigeti, R. Kellermayer, Hailey–Hailey disease and calcium: lessons from yeast, J. Invest. Dermatol. 123 (2004) 1195–1196. [9] R. Kellermayer, R. Szigeti, K.M. Keeling, et al., Aminoglycosides as potential pharmacogenetic agents in the treatment of Hailey–Hailey disease, J. Invest. Dermatol. 126 (2006) 229–231. [10] R. Szigeti, A. Miseta, R. Kellermayer, Calcium and magnesium competitively influence the growth of a PMR1 deficient Saccharomyces cerevisiae strain, FEMS Microbiol. Lett. 251 (2005) 333–339.
Richard Kellermayer ∗ Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, 6621 Fannin Street, CC1010.00, Houston, TX 77030-2399, USA ∗ Tel.:
+1 832 822 3131; fax: +1 832 825 3633. E-mail address: [email protected] 30 April 2007 Available online 17 August 2007