Functional insights into a neurodevelopmental disorder caused by missense variants in an RNA-binding protein, RBM10.

 

Kimihiko Oishi, MD

Professor and Chair of Pediatrics

Department of Pediatrics, The Jikei University School of Medicine

 

An increasing number of cases with neurodevelopmental disorders have been identified to be caused by variants in genes encoding RNA binding proteins. An RNA-binding motif protein, RBM10, is one of those proteins which is associated with a developmental genetic disorder, TARP syndrome (OMIM #311900). Loss-of-function variants in the RBM10 gene on the X chromosome cause TARP syndrome, characterized by the clinical tetrads of talipes equinovarus, atrial septal defect, Robin sequence, and persistent left superior vena cava in males. The incidence of this disease is very low, and no germline missense RBM10 variants have been previously reported. RBM10 is a ubiquitously expressed RNA binding protein and was initially suggested to be involved in tumorigenesis. But its biological roles are now recognized to be diverse, and it was found to be a key factor for controlling cell proliferation or apoptosis through the transcriptional regulation by alternative splicing events of multiple downstream genes. We have recently identified novel missense RBM10 variants in the RRM2 RNA-binding domain in male patients with developmental delays with some dysmorphic features. Their clinical symptoms were much milder than those described in the previously reported cases of TARP syndrome. By molecular analyses, we identified that those germline missense variants of RBM10 resulted in mild TARP syndrome due to altered downstream gene expressions through unique molecular mechanisms. Our findings highlight the importance of proper mRNA processing for human development and may facilitate a better understanding of the molecular developmental mechanism of RBM10. In this seminar, I will present the details of our recent project update and discuss the utility of comprehensive clinical genetic sequencing for rare undiagnosed genetic diseases.

 

Imagawa E, Konuma T, Cork EE, Diaz GA, Oishi K. A novel missense variant in RBM10 can cause a mild form of TARP syndrome with developmental delay and dysmorphic features. Clin. Genet. 98 (6) 606-612 doi: 10.1111/cge.13835 (2020)