TY  - JOUR
AU  - Hengel, Holger
AU  - Hannan, Shabab-Bin
AU  - Reich, Selina
AU  - Beijer, Danique
AU  - Roller, Johanna Rosa
AU  - Gilsbach, Bernd K
AU  - Gloeckner, Christian Johannes
AU  - Greene, Daniel
AU  - Timmann, Dagmar
AU  - Depienne, Christel
AU  - Mumford, Andrew
AU  - O'Driscoll, Mary
AU  - Nemeth, Andrea H
AU  - Lundberg, Julie
AU  - Rodan, Lance H
AU  - Bruel, Ange-Line
AU  - Delanne, Julian
AU  - Deconinck, Tine
AU  - Baets, Jonathan
AU  - Gan-Or, Ziv
AU  - Rouleau, Guy
AU  - Suchowersky, Oksana
AU  - Estiar, Mehrdad A
AU  - Reich, Stephen
AU  - Toro, Camilo
AU  - Züchner, Stephan
AU  - Hazan, Jamilé
AU  - Pétursson, Hjörvar
AU  - Harmuth, Florian
AU  - Bauer, Claudia
AU  - Bauer, Peter
AU  - Turro, Ernest
AU  - Lambright, David
AU  - Schöls, Ludger
AU  - Synofzik, Matthis
TI  - Heterozygous RAB3A variants cause cerebellar ataxia by a partial loss-of-function mechanism.
JO  - Brain
VL  - 148
IS  - 8
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2025-00910
SP  - 2812 - 2826
PY  - 2025
AB  - RAB3A encodes a small GTP-binding protein that is abundant in brain synaptic vesicles and crucial for the release of neurotransmitters and synaptic plasticity. Here, we identified RAB3A as a candidate gene for autosomal dominant cerebellar ataxia by two independent approaches: linkage in a large dominant ataxia family and, in parallel, an untargeted computational genetic association approach, analysing the 100 000 Genomes Project datasets. To validate the role of RAB3A in ataxia, we next screened large rare disease databases for rare heterozygous RAB3A variants in probands with ataxia features. In total, we identified 18 individuals from 10 unrelated families all sharing a cerebellar ataxia phenotype. Notably, 9 of the 10 families carried a recurrent variant in RAB3A, p.Arg83Trp, including one de novo occurrence. In addition, our screening revealed three families with a neurodevelopmental phenotype and three unique RAB3A variants, which were either de novo or loss-of-function variants. In line with the different RAB3A variant types, protein domains and predicted functional consequences, a comprehensive set of complementary methods was used to characterize the identified variants functionally. As expected, GTPase-activating protein (GAP)-dependent GTP hydrolysis was reduced for those two missense variants located in the GAP-binding domain of RAB3A (Arg83Trp and Tyr91Cys). In a Drosophila Rab3 loss-of-function model, these two missense variants also failed to rescue a synaptic phenotype. Overexpression of Rab3 variants in Drosophila wild-type background did not cause an obvious phenotype, making a dominant negative effect of these variants unlikely. Lastly, exploring interactors of RAB3A variants by using co-immunoprecipitation and mass spectrometry showed differential changes in variant-specific interactions with known RAB3A key regulatory and effector proteins. In sum, our results establish RAB3A as a neurological disease gene. It represents an autosomal dominant gene for cerebellar ataxia with different variants associated with disease, including the frequent reoccurring variant p.Arg83Trp. Our study sheds light on the variant-specific interactome of RAB3A. Finally, we suggest an association of RAB3A with a neurodevelopmental phenotype, as reported for variants in several RAB3A interaction partners and as seen in Rab3A-deficent mice, although this possible association warrants further investigation by future studies.
KW  - Humans
KW  - rab3A GTP-Binding Protein: genetics
KW  - rab3A GTP-Binding Protein: metabolism
KW  - Cerebellar Ataxia: genetics
KW  - Animals
KW  - Male
KW  - Female
KW  - Pedigree
KW  - Middle Aged
KW  - Heterozygote
KW  - Adult
KW  - Loss of Function Mutation: genetics
KW  - Phenotype
KW  - Bayesian statistical genetic association (Other)
KW  - GTPase (Other)
KW  - Rareservoir (Other)
KW  - genome sequencing (Other)
KW  - neurodevelopmental disorder (Other)
KW  - neurogenetic disease (Other)
KW  - rab3A GTP-Binding Protein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40166812
C2  - pmc:PMC12316009
DO  - DOI:10.1093/brain/awaf111
UR  - https://pub.dzne.de/record/280232
ER  -