Myotone Dystrophien - Aktueller Stand der molekularen Pathogenese

Zusammenfassung

Myotone Dystrophien (DM) sind die häufigsten dominant vererbten neuromuskulären Erkrankungen im Erwachsenenalter. Multisystemische Symptome betreffen Skelettmuskulatur, Gehirn, Auge, Herz und Endokrinum. Ätiologisch sind zwei genetische Loci mit einem DM-Phänotyp gekoppelt: der klassische Phänotyp (Curschmann-Steinert, DM1) ist Chromosom 19 zugeordnet und der Typ 2 (PROMM, Ricker disease, DM2) Chromosom 3. Als kausale Mutation wurde 1992 für DM1 ein expandiertes CTG repeat in der nicht translatierten 3'-Region des Dystrophia Myotonica-Protein-Kinase-Gen (DMPK), und 2001 für DM2 ein expandiertes CCTG repeat in Intron 1 des Zinkfinger-9-Gens (ZNF9) entdeckt. Eine 3. multisystemische Form (DM3?) mit einer frontotemporalen Demenz koppelt auf Chromosom 15. Pathogenetisch liegt bei den Manifestationsformen eine Ansammlung von CUG-/CCUG-Polyribonukleotiden und deren Bindungsproteinen im Zellkern und Zytoplasma vor, die die normale Prozessierung von RNA stören (gain of function) und aberrantes Spleißen von Prä-mRNAs auslösen, sodass u. a. gewebsspezifische, veränderte Proteinisoformen entstehen. Zusätzlich scheint eine Störung von Transkriptionsfaktoren vorzuliegen. Diese Übersicht setzt die multisystemischen Symptome der Erkrankungen in Bezug zu neuen Aspekten der molekularen RNA-Pathogenese.

Abstract

The multisystemic myotonic dystrophies encompass at least two clinical and molecular distinct forms, the classic Steinert's disease (DM1) and the new type (Ricker's disease, DM2) so far. Recently, a potential third form (DM3?) was described. In 1992, the mutation causing DM1 was identified as a CTG repeat in the DMPK Gene on Chromosome 19q, in 2001 the mutation causing DM2 was identified as a CCTG repeat in the ZNF-9 gene on chromosome 3q. Since the molecular mechanism seems to be based on a gain-of-function RNA mechanism, some of the multisystemic features could be drawn back to alternative and aberrant splicing of tissue specific genes, such as chloride channel, while others are still uncharacterised. This review focuses on the multisystemic clinical features and their new molecular pathogenesis.

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