Project Details
Projekt
Non-muscular actinopathies: Baraitser-Winter Cerebrofrontofacial syndrome and related disorders
Subject Area
Human Genetics
Term
from 2017 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 391987448
The human genome encodes six actin isoforms, which are produced in a temporal- and tissue-specific manner. It is through the dynamic cycling of monomeric G- and polymeric F-actin that cytoskeleton remodelling ensues, supporting active movement, tension generation and adaptation to external forces. The complexity of the actin-cytoskeleton and its regulatory systems, in combination with various technical issues, has long prevented efficient elucidation of the structural and functional consequences of pathogenic actin mutations. Recent developments in our ability to produce and characterize recombinant actin isoforms and actin binding proteins, resolve high-resolution F-actin structures, and obtain patient-derived cell cultures, create a unique opportunity where we can advance our understanding of actin role in health and disease to new levels. Baraitser-Winter Cerebrofrontofacial syndrome (BWCFF) is a complex developmental disorder with craniofacial, visceral and muscular involvement caused by mutations in ACTB and ACTG1, the genes encoding the two cytoskeletal isoforms of actin. We have ascertained 67 individuals with confirmed disease-causing mutations in ACTB and ACTG1. The majority of the patients presented with a multi-systemic disorder that includes a typical facial phenotype, while a smaller group lacks the dysmorphic facial features and shows milder developmental disabilities. Patients in this group, which we refer to as non-BWCFF, have either mutations in ACTB and suffer from thrombocytopenia or mutations in ACTG1 leading to progressive hearing deficits and movement disorders. Our preliminary experiments in patient fibroblasts indicate that there is a direct correlation between cellular morphology and function with the severity of the patients disease phenotype. Here, we aim to elucidate how these phenotypes are induced by mutations in ACTB and ACTG1. We intend to assess these effects of select mutations at the level of the purified mutant protein, alone and in complex with key binding partners; and at the cellular level, examining cellular morphology and dynamics, chromatin structure, and transcription profile. This data will be related to clinical symptoms observed in BWCFF and non-BWCFF patients. We expect this approach to reveal rules and patterns that link the mutation effects over several hierarchy levels to the disease phenotypes observed with different types of actinopathies. Moreover, we anticipate important new insights into the range and isoform-specificity of ACTB and ACTG1 dependent functions.
DFG Programme
Research Grants
