View Program - 63rd Annual Drosophila Research Conference

Myocardin-related transcription factor B (MRTF-B) is a member of a family of genes which serve to potentiate serum response factor (SRF)-dependent transcription and is highly conserved in both vertebrate and invertebrate model organisms. The MRTF-B protein is not currently associated with a human disease but has been shown to be highly expressed in all human tissues save the lung. Here we report a proband with a de novo variant in the second RPEL domain of MRTF-B with intellectual disability, minor dysmorphic features, expressive language delay, impulse control issues, and fine motor delay. We have generated a fly model of human MRTF-B, using a UAS construct carrying either the human reference or variant cDNA. Expression of the UAS-human variant cDNA under the control of the Nubbin-Gal4 driver was sufficient to induce significant morphological changes in the wing, while the expression of the human reference cDNA produced only minor changes in the posterior crossvein. Expression of Drosophila Mrtf using the Nubbin-Gal4 driver produced a similar change in crossvein length as was observed with the human reference. In Drosophila, the SRF ortholog is known as blistered (bs) and is known to suppress wing vein formation and promote the development of intervein cells. As exogenous co-expression of bs and Mrtf has been previously shown to significantly alter wing morphology, we also expressed our human reference and variant cDNA lines concurrently with a UAS-bs line. In these experiments we found that wing morphology was highly disrupted when bs and the reference human cDNA were co-expressed, while the co-expression of human variant cDNA and bs was lethal. Based on these findings, we sought and identified two additional probands with variants within or near the second RPEL domain. Expression of these additional variants using Nubbin-Gal4 produced changes in the posterior crossvein analogous to the changes observed when our human reference line was expressed. Taken together, these findings suggest that different residue changes within the RPEL domain of MRTF-B can have drastically different morphological effects in the fly wing, and our initial de novo variant may underly a novel disorder.

De novo variant in MRTF-B is associated with intellectual disability, minor dysmorphic features, expressive language delay, impulse control issues, and fine motor delay.