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000280232 0247_ $$2doi$$a10.1093/brain/awaf111
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000280232 1001_ $$0P:(DE-2719)2811940$$aHengel, Holger$$b0$$eFirst author
000280232 245__ $$aHeterozygous RAB3A variants cause cerebellar ataxia by a partial loss-of-function mechanism.
000280232 260__ $$aOxford$$bOxford Univ. Press$$c2025
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000280232 520__ $$aRAB3A 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.
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000280232 650_7 $$2Other$$aBayesian statistical genetic association
000280232 650_7 $$2Other$$aGTPase
000280232 650_7 $$2Other$$aRareservoir
000280232 650_7 $$2Other$$agenome sequencing
000280232 650_7 $$2Other$$aneurodevelopmental disorder
000280232 650_7 $$2Other$$aneurogenetic disease
000280232 650_7 $$0EC 3.6.5.2$$2NLM Chemicals$$arab3A GTP-Binding Protein
000280232 650_2 $$2MeSH$$aHumans
000280232 650_2 $$2MeSH$$arab3A GTP-Binding Protein: genetics
000280232 650_2 $$2MeSH$$arab3A GTP-Binding Protein: metabolism
000280232 650_2 $$2MeSH$$aCerebellar Ataxia: genetics
000280232 650_2 $$2MeSH$$aAnimals
000280232 650_2 $$2MeSH$$aMale
000280232 650_2 $$2MeSH$$aFemale
000280232 650_2 $$2MeSH$$aPedigree
000280232 650_2 $$2MeSH$$aMiddle Aged
000280232 650_2 $$2MeSH$$aHeterozygote
000280232 650_2 $$2MeSH$$aAdult
000280232 650_2 $$2MeSH$$aLoss of Function Mutation: genetics
000280232 650_2 $$2MeSH$$aPhenotype
000280232 7001_ $$0P:(DE-2719)9000570$$aHannan, Shabab-Bin$$b1
000280232 7001_ $$0P:(DE-2719)2813732$$aReich, Selina$$b2
000280232 7001_ $$0P:(DE-2719)9002605$$aBeijer, Danique$$b3$$udzne
000280232 7001_ $$0P:(DE-2719)9003395$$aRoller, Johanna Rosa$$b4$$udzne
000280232 7001_ $$0P:(DE-2719)2811745$$aGilsbach, Bernd K$$b5$$udzne
000280232 7001_ $$0P:(DE-2719)2811291$$aGloeckner, Christian Johannes$$b6$$udzne
000280232 7001_ $$aGreene, Daniel$$b7
000280232 7001_ $$aTimmann, Dagmar$$b8
000280232 7001_ $$00000-0002-7212-9554$$aDepienne, Christel$$b9
000280232 7001_ $$aMumford, Andrew$$b10
000280232 7001_ $$aO'Driscoll, Mary$$b11
000280232 7001_ $$aNemeth, Andrea H$$b12
000280232 7001_ $$aLundberg, Julie$$b13
000280232 7001_ $$aRodan, Lance H$$b14
000280232 7001_ $$aBruel, Ange-Line$$b15
000280232 7001_ $$aDelanne, Julian$$b16
000280232 7001_ $$aDeconinck, Tine$$b17
000280232 7001_ $$aBaets, Jonathan$$b18
000280232 7001_ $$00000-0003-0332-234X$$aGan-Or, Ziv$$b19
000280232 7001_ $$00000-0001-8403-1418$$aRouleau, Guy$$b20
000280232 7001_ $$aSuchowersky, Oksana$$b21
000280232 7001_ $$aEstiar, Mehrdad A$$b22
000280232 7001_ $$aReich, Stephen$$b23
000280232 7001_ $$aToro, Camilo$$b24
000280232 7001_ $$00000-0002-8498-5235$$aZüchner, Stephan$$b25
000280232 7001_ $$aHazan, Jamilé$$b26
000280232 7001_ $$aPétursson, Hjörvar$$b27
000280232 7001_ $$aHarmuth, Florian$$b28
000280232 7001_ $$aBauer, Claudia$$b29
000280232 7001_ $$aBauer, Peter$$b30
000280232 7001_ $$aTurro, Ernest$$b31
000280232 7001_ $$aLambright, David$$b32
000280232 7001_ $$0P:(DE-2719)2810795$$aSchöls, Ludger$$b33
000280232 7001_ $$0P:(DE-2719)2811275$$aSynofzik, Matthis$$b34$$eLast author
000280232 773__ $$0PERI:(DE-600)1474117-9$$a10.1093/brain/awaf111$$gVol. 148, no. 8, p. 2812 - 2826$$n8$$p2812 - 2826$$tBrain$$v148$$x0006-8950$$y2025
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