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Klin Monbl Augenheilkd 2000; 217(1): 43-51
DOI: 10.1055/s-2000-10382
KLINISCHE STUDIE

Georg Thieme Verlag Stuttgart · New York

Keratin-Gen-Mutationen als Ursache der Epitheldystrophie Meesmann-Wilke und autosomal dominanter Verhornungsstörungen der Haut[1]

Keratin gene mutations cause Meesmann's corneal dystrophy and autosomal dominant skin disorders of cornificationOle Swensson1 , Beate Swensson2 , Bernhard Nölle2 , Rainer Rochels2 , Bernhard Wannke3 , Hans-Jürgen Thiel3
  • 1 Klinik für Dermatologie und Venerologie, Christian-Albrechts-Universität Kiel, Schittenhelmstr. 7, 24105 Kiel (Direktor: Prof. Dr. med. Dr. h. c. E. Christophers)
  • 2 Klinik für Ophthalmologie, Christian-Albrechts-Universität Kiel, Hegewischstr. 2, 24105 Kiel (Direktor: Prof. Dr. med. R. Rochels)
  • 3 Augenklinik der Eberhard-Karls-Universität, Abteilung Augenheilkunde I, Schleichstr. 12 - 16, 72076 Tübingen (Direktor: Prof. Dr. med. H.-J. Thiel)
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Publication History

Publication Date:
31 December 2000 (online)

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Zusammenfassung

Hintergrund Die Epitheldystrophie Meesmann-Wilke (OMIM 122 100) ist eine seltene autosomal dominant erbliche Erkrankung des Hornhautepithels, die im frühen Kindesalter nachweisbar ist und beide Augen betrifft. Kennzeichen der Erkrankung ist eine in ihrem Verteilungsmuster variable Trübung des Hornhautepithels. Bei der Spaltlampenuntersuchung und im regredienten Licht geben sich monomorphe Opaleszenzen und intraepitheliale Bläschen zu erkennen. Weitere Erkrankungszeichen sind punktförmige Erosionen, Epiphora, gesteigerte Blendempfindlichkeit und Blepharospasmus. Der Visus ist zumeist nicht oder nur geringfügig beeinträchtigt. Histologisch zeigt sich eine gestörte Epithelschichtung, eine Vakuolisierung der Epithelzellen und eine intraepitheliale Vesikelbildung. Elektronenmikroskopisch lassen sich fibrogranuläre Ablagerungen im Zytoplasma der Epithelzellen nachweisen.

Ergebnisse Bei Nachkommen der von Meesmann und Wilke beschriebenen Merkmalsträger und weiteren betroffenen Familien konnte mittels genetischer Kopplungsanalyse gezeigt werden, dass der zugrunde liegende genetische Defekt im Bereich des Keratin Typ I Genclusters auf Chromosom 17 (17q12-21) lokalisiert ist. Molekulargenetische Untersuchungen an mehr als zehn Familien mit epithelialer Hornhautdystrophie wiesen nach, dass der Erkrankung in allen bisher untersuchten Fällen Mutationen der korneaspezifischen Keratine K3 und K12 zugrunde liegen.

Schlussfolgerungen Vergleichende Untersuchungen an autosomal dominant erblichen Verhornungsstörungen der Haut lassen vermuten, dass die bei der Meesmannschen Epitheldystrophie nachgewiesenen Keratingen-Mutationen einen dominant negativen Effekt auf die Keratinfilamentbildung ausüben. Die gestörte Filamentbildung führt zu intrazellulären Keratinverklumpungen, die sich als fibrogranuläre Ablagerung zu erkennen geben. Hieraus resultiert eine Minderung der mechanischen Widerstandsfähigkeit der betroffenen Epithelzellen und des epithelialen Zellverbandes. Ob Anomalien funktionell verwandter Strukturelemente des Zytoskeletts, wie beispielsweise desmosomale Proteine, in der Lage sind, einen der epithelialen Hornhautdystrophie Meesmann-Wilke ähnlichen Phänotyp zu induzieren, ist bislang ungeklärt.

Abkürzungen K, Keratin; OMIM, Online Mendelian Inheritance in Man

Literatursuche in Medline.

Background Meesmann's corneal dystrophy (OMIM 122 100) is a rare autosomal dominant disorder of the corneal epithelium. It manifests in early childhood and affects both eyes. The disease is characterized by variable patterned dot-like corneal opacities and intraepithelial vesicles, which can be seen by slit-lamp examination and retroillumination. Further signs include punctate erosions, lacrimation, photophobia, and blepharospasm. Vision is usually only slightly diminished. By histology, the corneal epithelium is irregularly thickened. It shows vacuolated epithelial cells and intraepithelial formation of vesicles. By electron microscopy fibrogranular aggregates are seen in the cytoplasm of epithelial cells.

Results Linkage analyses in descendants of the family described by Meesmann and Wilke and other affected kinships showed that the putative genetic defect locates within the keratin type I gene cluster on chromosome 17 (17q12-21). Molecular genetic analyses in more than ten affected families showed that mutations in the cornea-specific keratin genes K3 and K12 represent the causative genetic defects of the disease phenotype.

Conclusion Comparative studies in autosomal dominant skin disorders of cornification suggest that the mutations identified in patients with Meesmann's corneal dystrophy exert dominant negative effects on keratin filament assembly. Disturbed filament formation results in intracellular keratin clumping, identifiable as fibrogranular aggregates. As a result the mechanical resilience of the affected cells and the epithelial tissue appears markedly reduced. Whether abnormalities of functionally related structural proteins, e.g. desmosomal components, could result in a phenotype similar to Meesmann and Wilke's corneal dystrophy remains to be seen.

Abbreviations K, Keratin; OMIM, Online Mendelian Inheritance in ManLiterature search in Medline.

Schlüsselwörter

Hornhautdystrophie - Keratine - Mutationsanalyse - Epitheldystrophie Meesmann-Wilke

Key words

Corneal dystrophy - keratins - mutational analysis - epithelial dystrophy Meesmann-Wilke

1 Manuskript eingereicht am 28. 12. 99 und in der vorliegenden Form angenommen.

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1 Manuskript eingereicht am 28. 12. 99 und in der vorliegenden Form angenommen.

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