Abstract
Neurodevelopmental disorders (NDDs) are clinically and genetically extremely heterogeneous with shared phenotypes often associated with genes from the same networks. Mutations in TCF4, MEF2C, UBE3A, ZEB2 or ATRX cause phenotypically overlapping, syndromic forms of NDDs with severe intellectual disability, epilepsy and microcephaly. To characterize potential functional links between these genes/proteins, we screened for genetic interactions in Drosophila melanogaster. We induced ubiquitous or tissue specific knockdown or overexpression of each single orthologous gene (Da, Mef2, Ube3a, Zfh1, XNP) and in pairwise combinations. Subsequently, we assessed parameters such as lethality, wing and eye morphology, neuromuscular junction morphology, bang sensitivity and climbing behaviour in comparison between single and pairwise dosage manipulations. We found most stringent evidence for genetic interaction between Ube3a and Mef2 as simultaneous dosage manipulation in different tissues including glia, wing and eye resulted in multiple phenotype modifications. We subsequently found evidence for physical interaction between UBE3A and MEF2C also in human cells. Systematic pairwise assessment of the Drosophila orthologues of five genes implicated in clinically overlapping, severe NDDs and subsequent confirmation in a human cell line revealed interactions between UBE3A/Ube3a and MEF2C/Mef2, thus contributing to the characterization of the underlying molecular commonalities.
Highlights
Neurodevelopmental disorders (NDDs) are clinically and genetically extremely heterogeneous, and currently more than 1,000 genes have been implicated (SysID database[1])
PTHS, MRD20 and MOWS are caused by haploinsufficiency of TCF4, MEF2C or ZEB2, respectively, all
To evaluate the possibility of overlapping phenotypes resulting from dosage manipulation of Ube3a, Mef[2], Da, XNP or Zfh[1] and to identify quantifiable phenotypes for subsequent genetic interaction experiments, we induced knockdown or overexpression either ubiquitously or in several different tissues and evaluated parameters such as viability, morphological alterations, synapse development and gross neurological behaviour (Fig. 1b)
Summary
Neurodevelopmental disorders (NDDs) are clinically and genetically extremely heterogeneous, and currently more than 1,000 genes have been implicated (SysID database[1]). Phenotypically and biologically coherent modules within this large and heterogeneous group have been increasingly delineated, indicating that overlapping phenotypes are often caused by mutations in genes involved in the same molecular networks[1,2,3,4,5] This has been demonstrated mainly for well-defined pathways or complexes such as the RAS-MAPK-pathway[4] or the SWI/SNF chromatin remodelling complex[6], but is less characterized for disease genes involved in a broader biological context or process such as transcriptional regulation. These molecular commonalities might contribute to the clinically overlapping features of the investigated disorders
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