PUBLICATION
Usmani-Riazuddin Syndrome: Functional Characterization of a Novel c.196G>A Variant in the AP1G1 Gene and Phenotypic Insights Using Zebrafish as a Vertebrate Model
- Authors
- Imperatore, V., Mirarchi, A., Agolini, E., Astolfi, A., Barreca, M.L., Novelli, A., Vinciarelli, E., Ferretti, S., Zizioli, D., Borsani, G., Arcuri, C., Prontera, P.
- ID
- ZDB-PUB-251113-18
- Date
- 2025
- Source
- International Journal of Molecular Sciences 26: (Journal)
- Registered Authors
- Keywords
- AP1G1, USRIS, Usmani–Riazzudin syndrome, brain disorder, central nervous system, intellectual disability, locomotor behavior, neurodevelopmental delay, whole-exome sequencing, zebrafish
- MeSH Terms
-
- Female
- Mutation, Missense
- Adaptor Protein Complex 1*/genetics
- Adaptor Protein Complex 1*/metabolism
- Disease Models, Animal
- Animals
- Phenotype
- Humans
- Intellectual Disability*/genetics
- Zebrafish/genetics
- PubMed
- 41226632 Full text @ Int. J. Mol. Sci.
Citation
Imperatore, V., Mirarchi, A., Agolini, E., Astolfi, A., Barreca, M.L., Novelli, A., Vinciarelli, E., Ferretti, S., Zizioli, D., Borsani, G., Arcuri, C., Prontera, P. (2025) Usmani-Riazuddin Syndrome: Functional Characterization of a Novel c.196G>A Variant in the AP1G1 Gene and Phenotypic Insights Using Zebrafish as a Vertebrate Model. International Journal of Molecular Sciences. 26:.
Abstract
Adaptor Protein-1 (AP-1) is a heterotetrameric essential for intracellular vesicular trafficking and polarized localization of somato-dendritic proteins in neurons. Variants in the AP1G1 gene, encoding the gamma-1 subunit of adaptor-related protein complex 1 (AP1γ1), have recently been associated with Usmani-Riazuddin syndrome (USRISD, MIM#619467), a very rare human genetic disorder characterized by intellectual disability (ID), speech and neurodevelopmental delays. Here we report a novel variant (c.196G>A; p.Gly66Arg) identified by exome sequencing analysis in a young girl showing overlapping clinical features with USRIS, such as motor and speech delay, intellectual disability and abnormal aggressive behavior. In silico analysis of the missense de novo variant suggested an alteration in AP1G1 protein folding. Patient's fibroblasts have been studied with immunofluorescence techniques to analyze the intracellular distribution of AP-1. Zebrafish are widely regarded as an excellent vertebrate model for studying human disease pathogenesis, given their transparent embryonic development, ease of breeding, high genetic similarity to humans, and straightforward genetic manipulation. Leveraging these advantages, we investigated the phenotype, locomotor behavior, and CNS development in zebrafish embryos following the microinjection of human wild-type and mutated AP1G1 mRNAs at the one-cell stage. Knockout (KO) of the AP1G1 gene in zebrafish led to death at the gastrula stage. Lethality in the KO AP1G1 fish model was significantly rescued by injection of the human wild-type AP1G1 mRNA, but not by transcripts encoded by the Gly66Arg missense allele. The phenotype was also not rescued when ap1g1-/- zebrafish embryos were co-injected with both human wild-type and mutated mRNAs, supporting the dominant-negative effect of the new variant. In this study, we defined the effects of a new AP1G1 variant in cellular and animal models of Usmani-Riazzudin syndrome for future therapeutic approaches.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping