Abstract
The RNA-binding motif protein 10, RBM10, is an RNA splicing regulator essential for development. Loss-of-function RBM10 variants are associated with TARP syndrome, a severe X-linked recessive condition in males. We report a 3-year-old male with a mild phenotype, consisting of cleft palate, hypotonia, developmental delay, and minor dysmorphisms, associated with a missense RBM10 variant, c.943T>C, p.Ser315Pro, affecting the RRM2 RNA-binding domain. His clinical features were similar to a previously reported case associated with a missense variant. The p.Ser315Pro mutant protein was expressed normally in the nucleus, but its expression level and protein stability were slightly reduced. Nuclear magnetic resonance spectroscopy showed that the structure and the RNA-binding ability of the RRM2 domain with the p.Ser315Pro were unaffected. However, it affects the alternative splicing regulations of downstream genes, NUMB and TNRC6A, and its splicing alteration patterns were variable depending on target transcripts. In summary, a novel germline missense RBM10 p.Ser315Pro variant that causes functional changes in the expression of its downstream genes results in a non-lethal phenotype associated with developmental delays. The functional alteration effects depend on the residues affected by missense variants. Our findings are expected to bring broader insights into the RBM10-associated genotype-phenotype relationships by delineating the molecular mechanism of RBM10 functions.
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Data availability
Data are available from corresponding authors upon reasonable request.
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Acknowledgements
We would like to thank the patient and his family for contributing to this study and the personnel of Microscopy Core Facility at the Icahn School of Medicine at Mount Sinai.
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Conceptualization: EI, KO. Investigation: EI, LM, TK. Supervision: KO. Patient recruitment and consent acquisition: VKM, CN. Writing - original draft: EI, TK, KO. Writing - review and editing: all authors.
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It was a non-interventional single case report describing clinical data that was collected as part of routine clinical care. No research or non-clinical testing or evaluations were done on the patient or patient-derived samples. IRB approval was not required according to the institution’s policy (Central Michigan University School of Medicine), while written informed consent was obtained from the patient’s parents for the publication as stated above. The original study regarding the functional assays of the p.Pro322Leu variant was approved by the Institutional Review Board of Icahn School of Medicine at Mount Sinai (GCO# 05-1150, HS# 10-00584).
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Imagawa, E., Moreta, L., Misra, V.K. et al. Functional insight into a neurodevelopmental disorder caused by missense variants in an RNA-binding protein, RBM10. J Hum Genet 68, 643–648 (2023). https://doi.org/10.1038/s10038-023-01162-0
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DOI: https://doi.org/10.1038/s10038-023-01162-0
