Abstract
Mutations in RNA-binding proteins can lead to pleiotropic phenotypes including craniofacial, skeletal, limb, and neurological symptoms. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are involved in nucleic acid binding, transcription, and splicing through direct binding to DNA and RNA, or through interaction with other proteins in the spliceosome. We show a developmental role for Hnrnpul1 in zebrafish, resulting in reduced body and fin growth and missing bones. Defects in craniofacial tendon growth and adult-onset caudal scoliosis are also seen. We demonstrate a role for Hnrnpul1 in alternative splicing and transcriptional regulation using RNA-sequencing, particularly of genes involved in translation, ubiquitination, and DNA damage. Given its cross-species conservation and role in splicing, it would not be surprising if it had a role in human development. Whole-exome sequencing detected a homozygous frameshift variant in HNRNPUL1 in 2 siblings with congenital limb malformations, which is a candidate gene for their limb malformations. Zebrafish Hnrnpul1 mutants suggest an important developmental role of hnRNPUL1 and provide motivation for exploring the potential conservation of ancient regulatory circuits involving hnRNPUL1 in human development.
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Details
1 Department of Biochemistry and Molecular Biology, University of Calgary, Calgary, AB T2N 4N1, Canada; Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada
2 Department of Medical Genetics, University of Alberta, Edmonton, AB T6G 2R3, Canada
3 Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology, Barcelona 08003, Spain; Universitat Pompeu Fabra (UPF), Barcelona 08002, Spain
4 Alberta Children’s Hospital Research Institute, University of Calgary, Calgary, AB T2N 4N1, Canada; Department of Medical Genetics, University of Calgary, Calgary, AB T2N 4N1, Canada