mRNA Metabolism and Hereditary Disorders: A Tale of Surveillance and Escape

Abstract

The exploration of the molecular origin of hereditary diseases focused on genes and proteins for many years. Recently, mRNA has gained increasing attention. Most human genes contain introns and a considerable proportion of transcripts are not only alternatively spliced but also regulated posttranscriptionally in manifold ways. mRNA processing as well as a complex network of interactions between the steps of gene expression and associated quality control mechanisms are guided by a multitude of regulative mRNA sequence elements. Therefore it is not surprising that mutations of such elements can cause or modify human disease. The purpose of this review is the illustration of principles of physiological and dysregulated mRNA metabolism as well as a survey of new analytical tools and therapeutic approaches.

Zusammenfassung

Während über viele Jahre die Erforschung der molekularen Ursachen hereditärer Erkrankungen sich auf Gene und auf Proteine als wesentliche Funktionsträger der Zelle konzentrierte, ist die mRNA in jüngerer Zeit mehr in den Blickpunkt gerückt. Die meisten humanen Gene enthalten Introns, und ein erheblicher Anteil der Transkripte werden nicht nur alternativ gespleißt, sondern auf vielfältige Weise posttranskriptionell reguliert. Die Vorgänge der mRNA-Prozessierung, sowie ein komplexes Netzwerk von Interaktionen zwischen den einzelnen Schritten der Genexpression und damit assoziierten Qualitätskontrollmechanismen werden von einer Vielzahl von regulativen Sequenzelementen in der mRNA gesteuert. Daher ist es nicht überraschend, dass Mutationen, die solche Elemente betreffen, humane Erkrankungen verursachen oder modifizieren können. Ziel dieser Übersicht ist, die Prinzipien von physiologischem und pathologischem mRNA-Metabolismus darzustellen und einen Überblick über neue analytische Methoden und therapeutische Ansätze zu geben.

Key words

mRNA - hereditary disorders - NMD - mRNA surveillance - therapy

Schlüsselwörter

mRNA - hereditäre Erkrankungen - NMD - mRNA-Qualitätskontrolle - Therapie

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