Abstract
Purpose: The study aimed to investigate the role of PABPC1 in developmental delay (DD). Methods: Children were examined by geneticists and pediatricians. Variants were identified using exome sequencing and standard downstream bioinformatics pipelines. We performed in silico molecular modeling and coimmunoprecipitation to test if the variants affect the interaction between PABPC1 and PAIP2. We performed in utero electroporation of mouse embryo brains to enlighten the function of PABPC1. Results: We describe 4 probands with an overlapping phenotype of DD, expressive speech delay, and autistic features and heterozygous de novo variants that cluster in the PABP domain of PABPC1. Further symptoms were seizures and behavioral disorders. Molecular modeling predicted that the variants are pathogenic and would lead to decreased binding affinity to messenger RNA metabolism-related proteins, such as PAIP2. Coimmunoprecipitation confirmed this because it showed a significant weakening of the interaction between mutant PABPC1 and PAIP2. Electroporation of mouse embryo brains showed that Pabpc1 knockdown decreases the proliferation of neural progenitor cells. Wild-type Pabpc1 could rescue this disturbance, whereas 3 of the 4 variants did not. Conclusion: Pathogenic variants in the PABP domain lead to DD, possibly because of interference with the translation initiation and subsequently an impaired neurogenesis in cortical development.
| Original language | English |
|---|---|
| Pages (from-to) | 1761-1773 |
| Number of pages | 13 |
| Journal | Genetics in Medicine |
| Volume | 24 |
| Issue number | 8 |
| Early online date | 5 May 2022 |
| DOIs | |
| Publication status | Published - 1 Aug 2022 |
Bibliographical note
Funding Information:The authors would like to thank the families for their support and consent to publish this study. This work was supported by doctoral scholarship from the Faculty of Medicine at the University of Leipzig , the National Natural Science Foundation of China (81871079), and the grants from Hunan Provincial Government (2019RS2005, 2021jj10070) to H.G. H.G. was also supported by the Innovation-Driven Project of Central South University (2020CX042). S.S. received funding from the Dietmar Hopp Stiftung (grant 23011236). This work was partially supported by the High Performance Computing Center of Central South University.
Funding Information:
The authors would like to thank the families for their support and consent to publish this study. This work was supported by doctoral scholarship from the Faculty of Medicine at the University of Leipzig, the National Natural Science Foundation of China (81871079), and the grants from Hunan Provincial Government (2019RS2005, 2021jj10070) to H.G. H.G. was also supported by the Innovation-Driven Project of Central South University (2020CX042). S.S. received funding from the Dietmar Hopp Stiftung (grant 23011236). This work was partially supported by the High Performance Computing Center of Central South University. Conceptualization: M.W. X.J. R.A.J. H.G.; Data Curation: M.W. X.J. R.A.J. H.G.; Formal Analysis: M.W. X.J. R.A.J. H.G. H.S. S.T. X.D. J.C.; Investigation: A.B. S.S. J.L.L. I.B.M. M.A. H.S. S.T. X.D. J.C.; Resources: M.W. R.A.J, A.B, S.S. J.L.L. I.B.M. M.A.; Visualization: H.S. X.J. M.W.; Supervision: H.G. R.A.J.; Writing-original draft: M.W. X.J. R.A.J. H.G; Writing-review and editing: A.B. S.S. J.L.L. I.B.M. M.A. H.S. S.T. X.D. J.C. All probands were clinically examined by experienced pediatricians and/or human geneticists and were enrolled and sampled according to standard local practice in approved human subjects’ protocols as part of routine clinical care at the respective institutes. The project was approved by the ethics committee of the University of Leipzig, Germany (224/16-ek and 402/16-ek) and was conducted in concordance to the Declaration of Helsinki. Written informed consent of all examined probands or their legal representatives was obtained for the publication of findings and photos after advice and informing about the risks and benefits of the study. University of Washington. CADD v1.4. Accessed October 25, 2021. http://cadd.gs.washington.edu/, National Center for Biotechnology Information. Index of /pub/clinvar/vcf_GRCh38. Accessed October 25, 2021. https://ftp.ncbi.nlm.nih.gov/pub/clinvar/vcf_GRCh38/, Wellcome Sanger Institute. DECIPHER. Accessed October 25, 2021. https://decipher.sanger.ac.uk/, BHCMG Centers for Mendelian Genomics. GeneMatcher, Accessed November 1, 2021. https://genematcher.org/, Broad Institute of MIT and Harvard. gnomAD genome 3.0. Accessed November 01, 2021. http://gnomad.broadinstitute.org/downloads, Broad Institute of MIT and Harvard. GTEx v8. Accessed October 25, 2021. https://www.gtexportal.org/home/datasets, Radboudumc. MetaDome version 1.0.1. Accessed October 25, 2021. https://stuart.radboudumc.nl/metadome, Computational Biology Center, Memorial Sloan Kettering Cancer Center. MutationAssessor release 3. Accessed November 01, 2021. http://mutationassessor.org/, Berlin Institute of Health. MutationTaster 2, Accessed 2015. http://www.mutationtaster.org/, Johns Hopkins University. OMIM, Accessed October 25, 2021. https://omim.org/, String Consortium. STRING database. Accessed October 25, 2021. https://www.string-db.org/, National Library of Medicine. The National Center for Biotechnology Information (NCBI), Accessed October 25, 2021. https://www.ncbi.nlm.nih.gov/, University of California. UCSC Cell Browser (human cerebral cortex) v1.1.1. Accessed October 25, 2021. https://cells.ucsc.edu/, UniProt Consortium. UniProt database, Release 01.2019. Accessed October 25, 2021. https://www.uniprot.org/, Ensemble. Variant Effect Predictor (VEP) from ENSEMBL Release 104. Accessed November 01, 2021. https://www.ensembl.org/, University of Leipzig. WebAutoCasC version 1.0.1. Accessed October 25, 2021. https://autocasc.uni-leipzig.de/
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