Dysregulated zinc homeostasis in rare skin disorders

ABSTRACT

Introduction: Zinc (Zn) is an essential trace element required for normal skin homeostasis. Therefore, cutaneous changes are often observed in Zn-deficient patients. Acrodermatitis enteropathica (AE) and spondylocheirodysplastic Ehlers-Danlos syndrome (SCD-EDS) are rare genetic skin disorders led by disturbed normal Zn homeostasis due to mutations of Zn transporters, ZIP4 and ZIP13, respectively. Recent mechanistic investigations into Zn´s functions help to develop new therapeutic approaches for the disorders.

Areas covered: We reviewed the history, genetics, and current knowledge of pathogenic mechanism by mutated Zn transporter proteins for AE and SCD-EDS. We also discussed future prospects of therapeutics for these disorders.

Expert opinion: Zn supplementation has already been recognized as a useful adjuvant for established therapies for a large number of dermatological disorders, improving quality of life of patients. Future challenge focusing on the development of modifiers for Zn transporter activity, gene or stem cell-based therapy may yield better therapeutics in combination with Zn treatment, and contribute to deeper understandings of the pathogenic mechanism behind Zn-associated skin diseases.

KEYWORDS:

• Zinc
• zinc transporter
• keratinocyte
• fibroblast
• acrodermatitis enteropathica
• Ehlers-Danlos syndrome

Article highlights

• AE is a hereditary autosomal recessive disorder with cutaneous lesions caused by systemic Zn deficiency due to mutations of ZIP4 protein.

• Zn deficiency in AE patients causes inflammatory skin lesions by excess amount of ATP release from epidermal keratinocytes due to depletion of Langerhans cells, and Zn supplementation reverses the clinical manifestations.

• SCD-EDS is a hereditary disorder of connective tissue with skin heperelasticity caused by disturbed intracellular Zn distribution due to mutations of ZIP13 protein.

• ZIP13 properly controls connective tissue development by regulating nuclear translocation of SMAD transcription factors in BMP and TGF-β-mediated signaling pathways.

• Pathogenic mutations of ZIP13 promote degradation of the functional proteins via proteasomes, leading to SCD-EDS pathogenesis.

• At a cellular level, treatment with proteasome inhibitors can restore the reduced expression of pathogenic ZIP13 mutant proteins.

This box summarizes key points contained in the article.

Acknowledgment

We thank Drs. Toshio Hirano, Masaru Taniguchi, and Shigeo Koyasu for their generous support.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This study was supported by grants from KAKENHI (26462324, 17H04011; TF) of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT), the Sumitomo Foundation (TF), the Naito Foundation (TF), the Nestlé Nutrition Council Japan (TF), the Mitsubishi Foundation (TF), the Vehicle Racing Commemorative Foundation (TF), and Takeda Science Foundation (TF).