Journal article
A severe neurodevelopmental syndrome linked to a South Asian founder variant in the UFMylation adaptor CDK5RAP3
Acta neuropathologica, Vol.151(1), 48
2026
PMID: 42045457
Abstract
We investigated the pathogenicity of a homozygous intronic variant in CDK5RAP3, a key UFMylation adapter, in three individuals from two unrelated families with a lethal neurodevelopmental disorder. CDK5RAP3 variants have not been linked to human disorders to date; however, murine Cdk5rap3 knockout is embryonic lethal and variants in five other UFMylation components cause severe neurodevelopmental conditions. A segregating homozygous variant, chr17(GRCh38):g.47974691G > A, CDK5RAP3 NM_176096.3:c.334 + 243G > A, was identified by trio whole-genome and proband RNA sequencing in Family A and by trio whole-exome sequencing data reanalysis in Family B. Variant pathogenicity investigations included RT-PCR, Western blot, co-immunoprecipitation and (phospho)proteomics to assess transcript, protein and UFMylation complex effects. Antisense oligonucleotide-mediated rescue of CDK5RAP3 expression combined with proteomics and phosphoproteomics defined the mechanistic impact of CDK5RAP3 deficiency and rescue in amniocytes from an affected individual. All three affected individuals showed foetal growth restriction, foetal akinesia, pontocerebellar hypoplasia, arthrogryposis and hepatic pathology. CDK5RAP3 c.334 + 243G > A activates a cryptic donor splice-site causing pseudoexon/intron inclusion triggering nonsense-mediated decay and deficiency of full-length CDK5RAP3 (NP_788276.1), while potentially allowing retained expression of C-terminal alternative isoforms. Co-immunoprecipitation revealed only full-length CDK5RAP3 binds UFL1, whereas C-terminal isoforms cannot. Primary amniocytes showed CDK5RAP3 deficiency was associated with impaired UFMylation of known substrates, RPL26 and UFBP1. Proteomic and phosphoproteomic analyses revealed dysregulation of extracellular matrix organisation, cell adhesion, mitotic/genome stability pathways, cytoskeletal networks and neuronal guidance, which were reversed by restoration of canonical CDK5RAP3 expression via splice-correcting antisense oligonucleotides. Phosphoproteomic data implicate CDK5RAP3 as an upstream regulator of UFL1 S462 phosphorylation, known to be regulated by Ataxia-telangiectasia mutated (ATM) signalling. Our findings provide strong evidence linking deficiency of full-length CDK5RAP3 to severe neurodevelopmental, liver and muscle dysfunction. This study further highlights the therapeutic potential of ASO-based deep-intronic splicing defect correction.
Details
- Title
- A severe neurodevelopmental syndrome linked to a South Asian founder variant in the UFMylation adaptor CDK5RAP3
- Authors/Creators
- Michaela Yuen - The University of SydneyKatharine Zhang - The University of SydneyRhett G. Marchant - The University of SydneyRyosuke Ishimura - Juntendo UniversityMark Graham - Children's Medical Research InstituteMay Aung-Htut - Murdoch UniversitySamantha Bryen - Garvan Institute of Medical ResearchRocio Rius - Garvan Institute of Medical ResearchLee Marshall - Children's Medical Research InstituteNader Aryamanesh - Children's Medical Research InstituteGregory Dziaduch - The University of SydneyHimanshu Joshi - The University of SydneyBen Weisburd - Broad InstituteSteve D. Wilton - Murdoch UniversityMeredith Wilson - The University of SydneyRussell Gear - Mercy Hospital for WomenLucy Hennington - Mercy Hospital for WomenStephanie Lau - Austin HealthHelen Doyle - Children's Hospital at WestmeadRichard J. Leventer - Royal Children's HospitalMichael Krivanek - Children's Hospital at WestmeadSusan M. White - The University of MelbourneSarah A. Sandaradura - Children's Hospital at WestmeadMasaaki Komatsu - Juntendo UniversityFrances J. Evesson - The University of SydneySandra T. Cooper - Children's Hospital at Westmead
- Publication Details
- Acta neuropathologica, Vol.151(1), 48
- Publisher
- Springer Berlin Heidelberg
- Number of pages
- 22
- Grant note
- Luminesce Alliance (Sydney Children’s Hospitals Network; Children’s Medical Research Institute; Children’s Cancer Institute; University of Sydney; UNSW Sydney) Children’s Medical Research Institute “Jeans for Genes” Foundation The University of Sydney University of Sydney (https://doi.org/10.13039/501100001774) MRF2016906; Rapid Applied Research Translation Program and Genomics Health Futures Mission: MRF2015930, MRF2032931 / Medical Research Future Fund (https://doi.org/10.13039/501100025520) GNT1121651; GNT2009982; NHMRC Investigator Grants GNT1116974, GNT2017952; NHMRC Research Grant GNT2002640 / National Health and Medical Research Council (https://doi.org/10.13039/501100000925)
- Identifiers
- 991005878895107891
- Copyright
- © The Author(s) 2026
- Murdoch Affiliation
- Personalised Medicine Centre
- Language
- English
- Resource Type
- Journal article
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