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Projekt Druckansicht

Nicht-muskuläre Aktinopathien: Baraitser-Winter Cerebrofrontofaciales Syndrom und verwandte Erkrankungen

Fachliche Zuordnung Humangenetik
Förderung Förderung von 2017 bis 2022
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 391987448
 
Erstellungsjahr 2022

Zusammenfassung der Projektergebnisse

ACTB and ACTG1 encode the cytoskeletal beta- and gamma-actin isoforms. The reasons for the great diversity of disease patterns caused by mutations in these ubiquitously expressed genes have so far remained poorly understood. We compiled and analyzed data from 270 individuals with putative pathogenic ACTB/ACTG1 variants. The resulting findings show that ACTB pLOF SNVs or small deletions tend to cause a mild neurodevelopmental-malformation syndrome; ACTG1 pLOF SNVs or small deletions are either benign or increase susceptibility for neurodevelopmental problems; ACTB missense/in-frame variants (MVs) cause Baraitser-Winter-Cerebrofrontofacial syndrome (ACTB- related BWCFFS) or dystonia-deafness syndrome (a single recurrent MV) or a disorder that is phenotypically similar to that caused by pLOF ACTB variants; ACTG1 MVs cause ACTG1-related BWCFFS or isolated deafness or likely isolated colobomas. Furthermore, a set of pathogenic ACTB/ACTG1 variants remained phenotypically unclassified. Expression studies in cells from patients with ACTB pLOF variants showed normal levels of ACTB but significant upregulation of ACTA2, suggesting that the underlying mechanism is mediated by impaired transcriptional adaptation. Biochemical studies showed that most ACTB/ACTG1 MVs interfere with actin polymerization/ depolymerization and/or disrupt actin-myosin interactions, suggesting dominant negative effects. Some ACTB MVs causing a ‘ACTB-pLOF phenotype’ resulted in protein degradation, suggesting functional haploinsufficiency as the underlying disease mechanism. Mice with BWCCFS variants were embryonic lethal. We have defined at least eight diseases caused by ACTB/ACTG1 variants and outlined their putative genotype-disease relationships. We propose to group these diseases together as "non-muscle actinopathies". Our findings shed light on the diversity of mechanisms underlying the non-muscle actinopathies and provide a strong basis for the development of new therapeutic approaches.

Projektbezogene Publikationen (Auswahl)

 
 

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