Zusammenfassung
Transkriptionsfaktoren sind entscheidende Regulatoren der Embryonalentwicklung, da sie die Genexpression in jeder Zelle kontrollieren. Mutationen in Transkriptionsfaktoren liegen häufig angeborenen Entwicklungsdefekten zugrunde, jedoch ist die funktionelle Einschätzung der Pathogenität einzelner Transkriptionsfaktorvarianten anspruchsvoll, da die molekulare Funktionsweise von Transkriptionsfaktoren nicht vollkommen verstanden ist. Besonders Gain-of-Function-Mutationen führen häufig zu neuen, unerwarteten Phänotypen, deren funktionelle Charakterisierung eine Herausforderung darstellt. Die im letzten Jahrzehnt entwickelte ChIP-seq-Technologie ermöglicht es, die molekularen Mechanismen zu unterscheiden, welche Transkriptionsfaktor-assoziierten Krankheiten zugrunde liegen. Dieser Artikel fasst die molekularen Pathomechanismen diverser Transkriptionsfaktormutationen zusammen und versucht einen molekularbiologischen Rahmen für die Bewertung neuer Transkriptionsfaktormutationen zu geben.
Abstract
Transcription factors (TF) are key regulators that control the cell-type-specific gene expression in each individual cell and are crucial for the coordination of embryonic development. Mutations in TFs frequently underlie heritable developmental defects; however, the functional characterization of a variant TF is challenging, since the exact molecular mechanisms by which TFs exert their function are not fully understood. In particular, gain-of-function mutations can lead to novel phenotypes that are difficult to characterize functionally. Recent technological advances, in particular ChIP-seq, have enabled experimental approaches that can distinguish between distinct molecular mechanisms underlying TF-associated diseases. This article reviews the molecular pathomechanisms underlying various TF mutations and proposes approaches to previously unknown TF mutations.
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Ibrahim, D. Missense-Mutationen in Transkriptionsfaktoren. medgen 27, 1–6 (2015). https://doi.org/10.1007/s11825-015-0034-6
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DOI: https://doi.org/10.1007/s11825-015-0034-6