Darier disease : A disease model of impaired calcium homeostasis in the skin

Savignac, Magali; Edir, Anissa; Simón, Marina; Hovnanian, Alain

doi:10.1016/j.bbamcr.2010.12.006

Cited by 75 publications

(94 citation statements)

References 69 publications

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“…The authors postulated that haploinsufficiency of this riboflavin transporter causes riboflavin deficiency, and when coupled with nutritional riboflavin deficiency in pregnancy, could result in the transient riboflavin-responsive disease observed in the newborn infant. (b) Darier's disease, a skin disease characterized by dark crusty patches on the skin (dyskeratosis folicularis), is inherited in an autosomal dominant manner caused by heterozygous inactivating mutations in the ATP2A2 gene (31). The latter encodes for the SERCA Ca 2ϩ -ATPase, which serves as an ATP-driven intracellular Ca 2ϩ pump located in the ER, hence actively concentrating Ca 2ϩ into the ER lumen.…”

Section: Znt4mentioning

confidence: 99%

Molecular Basis of Transient Neonatal Zinc Deficiency

Golan¹,

Itsumura

Glaser³

et al. 2016

Journal of Biological Chemistry

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A gradually increasing number of transient neonatal zinc deficiency (TNZD) cases was recently reported, all of which were associated with inactivating ZnT2 mutations. Here we characterized the impact of three novel heterozygous ZnT2 mutations G280R, T312M, and E355Q, which cause TNZD in exclusively breastfed infants of Japanese mothers. We used the bimolecular fluorescence complementation (BiFC) assay to provide direct visual evidence for the in situ dimerization of these ZnT2 mutants, and to explore their subcellular localization. Moreover, using three complementary functional assays, zinc accumulation using BiFC-Zinquin and Zinpyr-1 fluorescence as well as zinc toxicity assay, we determined the impact of these ZnT2 mutations on vesicular zinc accumulation. Although all three mutants formed homodimers with the wild type (WT) ZnT2 and retained substantial vesicular localization, as well as vesicular zinc accumulation, they had no dominant-negative effect over the WT ZnT2. Furthermore, using advanced bioinformatics, structural modeling, and site-directed mutagenesis we found that these mutations localized at key residues, which play an important physiological role in zinc coordination (G280R and E355Q) and zinc permeation (T312M). Collectively, our findings establish that some heterozygous loss of function ZnT2 mutations disrupt zinc binding and zinc permeation, thereby suggesting a haploinsufficiency state for the unaffected WT ZnT2 allele in TNZD pathogenesis. These results highlight the burning need for the development of a suitable genetic screen for the early diagnosis of TNZD to prevent morbidity.In the past 50 years, the key role of zinc in human health was established (1). Zinc is crucial for central physiological processes including DNA and protein synthesis, enzyme activity, intracellular signaling, immune function, fertility, as well as growth and development (1-3). Zinc homeostasis is primarily regulated by two zinc transporter families as well as by zincbinding proteins. The SLC39A gene family encodes for ZIP1-14 transporters, which are responsible for zinc uptake into the cytosol from the extracellular fluid or from intracellular vesicles (4). In contrast, the SLC30A gene family encodes for the transporters ZnT1-10, which are responsible for zinc secretion from the cytosol to intracellular organelles or through the plasma membrane outside the cells (2, 4).The recent position of the Academy of Nutrition and Dietetics (5) is that breastfeeding in the first 6 months of life can provide adequate micronutrients and macronutrients for optimal growth and development. This statement is correct for the vast majority of infants around the world. However, recent reports indicate that some exclusively breastfed infants suffer from severe zinc deficiency due to lack of zinc in the breast milk they consume (6 -11). These cases were referred to as transient neonatal zinc deficiency (TNZD), 4 as the symptoms can be treated with zinc supplementation to the diet of the infant (12, 13). In contrast to TNZD, which appe...

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Section: Znt4mentioning

confidence: 99%

Molecular Basis of Transient Neonatal Zinc Deficiency

Golan¹,

Itsumura

Glaser³

et al. 2016

Journal of Biological Chemistry

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“…9 There are three paralogs of SERCA, SERCA1-3, encoded by ATP2A1-3, respectively. Mutations of SERCA1 cause Brody myopathy, a disorder of skeletal muscle contractions, 10 13,14 Haploinsufficiency is thought to underlie the autosomal dominant inheritance of DD. 6 It is thought that a mutation in one allele of ATP2A2 results in half levels of functional SERCA2, and further reductions in mRNA and protein expression from intact ATP2A2 allele leads to impaired regulation of intracellular calcium concentration and the subsequent development of disease.…”

mentioning

confidence: 99%

Darier disease

Takagi

and

Ikeda

2016

The Journal of Dermatology

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Darier disease (DD) is a type of inherited keratinizing disorder that exhibits autosomal dominant inheritance. DD is caused by the mutations of ATP2A2, which encodes an endoplasmic reticulum calcium pump, sarco/endoplasmic reticulum ATPase type 2 (SERCA2). DD often develops in childhood, persists through adolescence, and causes small papules predominantly in seborrheic areas such as the face, chest and back. Further, scales and scabs may gradually develop. DD may be accompanied by non-dermal symptoms, including psychiatric symptoms. Histologically, DD is characterized by corps ronds and grains in addition to suprabasal cleavage. There are no currently validated curative treatments available for DD, with the majority of cases treated symptomatically. Despite demonstrating efficacy in the treatment of DD, the use of oral retinoids has been limited due to the association with various adverse effects.

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“…Our result found significantly lower level of calcium in acne patients when compared to control subjects (p<0.001) which is supported by a previous study where decreased concentration of calcium in endoplasmic reticulum was found to be the cause of darier keratinocytes, one kind of skin disease. 30 Though potentially harmful, reactive oxygen species (ROS) are essential for biological functions. 31 Lipid peroxidation, which is harmful to health, occurs through a free radical chain reaction mechanism where oxygen acts as a vital element.…”

Section: Resultsmentioning

confidence: 99%

Effect of Serum Trace Elements, Macro-minerals and Antioxidants in Acne Vulgaris Patients: A Case-Control Study

Ahmed

Ali

Islam

et al. 2017

Dhaka Univ. J. Pharm. Sci

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Acne vulgaris is a chronic skin disease with multifaceted cause. The exact etiology and pathogenesis of acne are yet to be established completely and various causative factors are considered as pathogenic mechanisms in the development of this disorder. We designed a study to determine the extent of serum trace elements, macrominerals and antioxidants in patients with acne, and thereby, to find the pathophysiological correlations, if any. Serum trace elements and macro-minerals were determined by flame atomic absorption spectroscopy. RP-HPLC was used to quantify antioxidants. Significantly (p<0.05) decreased level of zinc (1.90±0.06 vs. 2.17±0.09 mg/L), calcium (115.64±4.84 vs. 197.05±7.11 mg/L) and vitamin A (0.2±0.06 vs. 0.86±0.26 µmol/L) was found in patient when compared with the corresponding controls. This investigation suggests a commendable association between the pathogenesis of acne vulgaris with the reduced level of zinc, calcium and vitamin A which could well be used as a diagnostic tool for acne vulgaris.

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Darier disease : A disease model of impaired calcium homeostasis in the skin

Cited by 75 publications

References 69 publications

Molecular Basis of Transient Neonatal Zinc Deficiency

Molecular Basis of Transient Neonatal Zinc Deficiency

Darier disease

Effect of Serum Trace Elements, Macro-minerals and Antioxidants in Acne Vulgaris Patients: A Case-Control Study

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