Johann Bauer

A Compound Heterozygous One Amino-Acid Insertion/Nonsense Mutation in the Plectin Gene Causes Epidermolysis Bullosa Simplex with Plectin Deficiency

Plectin is a cytoskeleton linker protein expressed in a variety of tissues including skin, muscle, and nerves. Mutations in its gene are associated with epidermolysis bullosa simplex with late-onset muscular dystrophy. Whereas in most of these patients the pathogenic events are mediated by nonsense-mediated mRNA decay, the consequences of an in-frame mutation are less clear. We analyzed a patient with compound heterozygosity for a 3-bp insertion at position 1287 leading to the insertion of leucine as well as the missense mutation Q1518X leading to a stop codon. The presence of plectin mRNA was demonstrated by a RNase protection assay. However, a marked reduction of plectin protein was found using immunofluorescence microscopy of the patients skin and Western blot analysis of the patients cultured keratinocytes. The loss of plectin protein was associated with morphological alterations in plectin-containing structures of the dermo-epidermal junction, in skeletal muscle, and in nerves as detected by electron microscopy. In an in vitro overlay assay using recombinant plectin peptides spanning exons 2 to 15 the insertion of leucine resulted in markedly increased self-aggregation of plectin peptides. These results describe for the first time the functional consequences of an in-frame insertion mutation in humans.

Genetik der atopischen Dermatitis

ZusammenfassungDie atopische Dermatitis (AD) ist eine häufige multifaktorielle Hauterkrankung mit starkem genetischem Hintergrund. Störungen in der epidermalen Barriere nehmen pathophysiologisch eine zentrale Stellung ein und sind teils zurückzuführen auf Null-Mutationen im Filaggrin-kodierenden Gen (FLG), einem essenziellen Strukturprotein des Stratum corneum. Eine gestörte Barrierefunktion ist eng verknüpft mit chronischer Immunaktivierung in der Haut im Zuge einer systemischen allergischen Reaktion. Es bestehen aber auch Abnormalitäten in den Immunantworten selbst. So konnten in den letzten Jahren, vor allem mittels genomweiter Studien, multiple, mit AD assoziierte Gene identifiziert werden, die unter anderem an Aufbau und Funktion der Hautbarriere, an der epidermalen Proliferation sowie Differenzierung, am Lipidmetabolismus und an der Immunantwort beteiligt sind. In diesem Artikel diskutieren wir die rezenten Erkenntnisse aus dem Bereich der Genetik der atopischen Dermatitis, ihre pathophysiologischen Konsequenzen und mögliche therapeutische Anwendungen.AbstractAtopic dermatitis is a common multifactorial skin disease showing a strong genetic background. A widespread abnormality in cutaneous barrier function seems to be pivotal in the pathogenesis, mainly attributed to loss-of-function mutations in the gene encoding filaggrin (FLG) that plays a decisive role in the skin barrier formation. A defective permeability barrier is strongly linked to chronic immune activation in the skin during systemic allergic reactions. Additionally, there are also abnormalities in the immune response itself. In recent years genome-wide association studies have enabled the identification of multiple genes involved in the formation and function of the cutaneous barrier, epidermal proliferation and differentiation, cutaneous lipid metabolism and in the response of the immune system. In this article we discuss recent genetic findings, their pathophysiological consequences and potential therapeutic implications.

Generalized Severe Junctional Epidermolysis Bullosa

The generalized severe subtype of junctional EB (formerly junctional EB Herlitz type) is the usually most severe lethal variant of the EB group of mechanobullous genodermatoses. Extreme blistering of the skin and mucous membranes and impaired wound healing lead to chronic erosions and formation of exuberant granulation tissue which, in addition to pigmentary changes, nail anomalies, and dental hypoplasia, are clinical hallmarks of the disease. Complications arising from numerous extracutaneous manifestations involving, for instance, the eye and gastrointestinal, laryngeal, and genitourinary tract also account for the devastatingly high morbidity and mortality in early childhood.

Plectin in Epidermolysis Bullosa and Autoimmune, Bullous Diseases

Cytoskeletal networks are composed of microtubules, actin filaments, and intermediate filaments. Cytolinker proteins like plectin connect these cytoskeletal elements to membrane-based adhesion complexes. Plectin is abundantly expressed in a wide variety of mammalian cells and tissues including muscles, epithelia, and nerve tissues. In the skin it appears to be a component of both hemidesmosomes and desmosomes. The plectin polypeptide is approximately 500 kDa in size, and it features a multidomain structure, including an aminoterminal actin-binding domain and a carboxyterminal intermediate filament-binding domain. Mutations in the gene coding for PLEC lead to pathological conditions with many different phenotypes, referred to as hereditary recessive forms of epidermolysis bullosa simplex combined with muscle dystrophy (EBS-MD), pyloric atresia (EBS-PA), myasthenic syndrome (EBS-MD-MyS), and limb-girdle muscular dystrophy (LGMD2Q) as well as dominant phenotypes characterized as EBS-Ogna. In addition, rare forms of paraneoplastic pemphigus (PNP) and epidermolysis bullosa acquisita (EBA) occur as autoimmune, bullous diseases.

Ungewöhnliche Manifestationen blasenbildender Dermatosen

Zahlreiche Proteine des Halteapparates Desmosom (Abb. 1) sowie der Adhasionseinrichtung Hemidesmosom der dermo-epidermalen Basalmembranzone (BMZ) (Abb. 2) sind in den letzten Jahren in Bezug auf Struktur und Funktionen charakterisiert worden. Bei der grosen Gruppe der hereditaren Epidermolysis-bullosa-Erkrankungen finden sich krankheitsbedingende Mutationen in den Genen dieser Ko- und Adhasionsmolekule, bei den bullosen Autoimmunerkrankungen werden sie durch Autoimmunmechanismen im Aufbau gestort oder zerstort. Die Identifikation von Mutationen bei Epidermolysis-bullosa-hereditaria-Patientlnnen lasst eine genaue Klassifikation [5] der jeweils vorliegenden Genodermatose zu, wie dies in gleicher Weise die Bestimmung eines Strukturproteins als Zielantigen eines autoimmunen Prozesses mit Hilfe der Immunoblot-/Immunprazipitations- oder ELISA-Technik ermoglicht [1].