Invited review article
Plectin-related skin diseases

https://doi.org/10.1016/j.jdermsci.2014.11.005Get rights and content

Highlights

Abstract

Plectin has been characterized as a linker protein that is expressed in many cell types and is distinctive in various isoforms in the N-terminus and around the rod domain due to complicated alternative splicing of PLEC, the gene encoding plectin. Plectin deficiency causes autosomal recessive epidermolysis bullosa simplex (EBS) with involvement of the skin and other organs, such as muscle and gastrointestinal tract, depending on the expression pattern of the defective protein. In addition, a point mutation in the rod domain of plectin leads to autosomal dominant EBS, called as EBS-Ogna. Plectin can be targeted by circulating autoantibodies in subepidermal autoimmune blistering diseases. This review summarizes plectin-related skin diseases, from congenital to autoimmune disorders.

Introduction

Plectin is a versatile linker protein that is expressed ubiquitously in many tissues, including skin, muscle and tissues of the nervous system. Plectin was originally characterized as an intermediate filament (IF)-linker protein, but it also serves as a binding partner to actin, microtubules and other membranous proteins, including hemidesmosomes and focal contact proteins [1], [2]. In studies of plectin, the complexity mostly derives from the diversity of its isoforms. In humans, several splicing transcripts at the 5′ end of PLEC, which encodes plectin, lead to plectin 1 and 1a to 1 g isoforms in which the first coding exons are mutually distinct (Fig. 1) (Table 1) [3]. Each isoform tends to have a preference for cell-type-specific or organelle-specific expression: isoform 1 for nucleus/ER membrane [4], 1a for hemidesmosomes in epidermal keratinocytes [5], 1b for mitochondria [4], [6], 1c for microtubules [7], 1d for the Z-disk in skeletal muscle [8] and 1f for focal adhesion contacts [4]. It is noteworthy that the nomenclature of PLEC mutations is based on the numbering of the coding sequences of transcript variant 1 (NM_000445), which encodes plectin 1c [9], unless the mutations occur in the other isoform-specific first coding exons (e.g., exon 1a, exon 1f) [10], [11]. In addition to 5′ splicing diversity, exon 31 of PLEC, which encodes the rod domain of plectin, can be spliced out in the rodless transcripts (Fig. 2) [12]. The basic biology of plectin has been recently reviewed from Dr. Wiche's group [1], [2], and he and his collaborators have greatly contributed to this field. Accordingly, this review focuses on the pathological aspects of plectin in skin diseases, such as in congenital and autoimmune blistering diseases.

Section snippets

Epidermolysis bullosa

Epidermolysis bullosa (EB) is a heterogeneous group of disorders characterized by congenital skin fragility and blister formation. Mutations in the genes encoding basement-membrane-zone (BMZ) proteins or other junctional proteins are responsible for EB phenotypes. EB has three major types and one minor type, depending on the ultrastructural level of skin detachment: EB simplex (EBS; cell lysis of basal or spinous layers), junctional EB (JEB; skin separation at the lamina lucida), dystrophic EB

Autoimmune blistering diseases with autoantibodies to plectin

Autoimmune blistering diseases are a group of disorders in which circulating autoantibodies target BMZ or desmosomal proteins and cause skin fragility. In addition to the major autoantigens such as desmoglein 1/3 in pemphigus and COL17 in bullous pemphigoid (BP), plectin has been listed as a protein targeted by circulating autoantibodies. Circulating anti-plectin antibodies were first detected in paraneoplastic pemphigus (PNP) patients [47], [48]. In line with this, 23 out of 28 PNP patients

Concluding remarks

Tremendous advances regarding plectin-related skin diseases have been achieved in the past two decades; however, many unsolved problems remain, mostly those discussed above. Table 3 summarizes the unsolved questions in this field. Furthermore, the development of treatment modalities for plectin-related EBS is essential. This is particularly true for EBS-PA, which typically leads to early demise even when pyloric atresia is surgically corrected. Bone marrow transplantation has been tried for JEB

Funding source

None.

Acknowledgements

I thank Drs. Hiroshi Shimizu and Wataru Nishie (Hokkaido University Graduate School of Medicine, Sapporo, Japan) for their continuous encouragement and support and Ms. Meari Yoshida for assistance in preparing the tables.

Ken Natsuga (M.D., Ph.D.) is a dermatologist at the Hokkaido University Graduate School of Medicine in Sapporo, Japan. He received his M.D. degree from the Hokkaido University School of Medicine in 2003. He researched the pathomechanisms of epidermolysis bullosa and bullous pemphigoid and received his Ph.D. degree from the Hokkaido University Graduate School of Medicine in 2010. He worked as a postdoctoral researcher at Cancer Research UK in Cambridge, U.K., from 2010 to 2012 under the

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    Ken Natsuga (M.D., Ph.D.) is a dermatologist at the Hokkaido University Graduate School of Medicine in Sapporo, Japan. He received his M.D. degree from the Hokkaido University School of Medicine in 2003. He researched the pathomechanisms of epidermolysis bullosa and bullous pemphigoid and received his Ph.D. degree from the Hokkaido University Graduate School of Medicine in 2010. He worked as a postdoctoral researcher at Cancer Research UK in Cambridge, U.K., from 2010 to 2012 under the supervision of Prof. Fiona Watt. He received a postdoctoral fellowship for research abroad from the JSPS during his stay in the U.K. After returning to Japan, he was appointed as an assistant professor in the Department of Dermatology, Hokkaido University Graduate School of Medicine, chaired by Prof. Hiroshi Shimizu. His research interests include blistering diseases, keratinocyte differentiation and skin microbiota.

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