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| Ataxia v2.14 | ATL2 | chirag patel Marked gene: ATL2 as ready | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia v2.14 | ATL2 | chirag patel Gene: atl2 has been classified as Red List (Low Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ataxia v2.14 | ATL2 |
chirag patel gene: ATL2 was added gene: ATL2 was added to Ataxia. Sources: Other Mode of inheritance for gene: ATL2 was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Phenotypes for gene: ATL2 were set to Cerebellar ataxia, MONDO:0000437, ATL2-related Mode of pathogenicity for gene: ATL2 was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: ATL2 was set to RED Added comment: ESHG 2026 7 living individuals from 1 large multigeneration family presenting with early onset (<20yrs but slowly progressive) ataxia, dysarthria, and cerebellar atrophy. WGS (SR and LR) identified a rare heterozygous 2-bp deletion variant in the ATL2 gene. The variant is deeply intronic in the canonical transcript but leads to a frameshift in an alternate transcript (ATL2-2, NM_001330461.2:c.1208_1209del, p.(Arg403Thrfs*6)), which is predominantly expressed in the brain and cerebellum. The same variant seen in 2 other unrelated families with dominant cerebellar ataxia. The variant is positioned in the last exon of this transcript, and it is not expected to cause nonsense-mediated decay but likely leads to a protein with an altered C-terminus. Functional analyses were conducted in ATL2/3 double knockout Cos7 cells with different ATL2 isoforms being reintroduced and subsequent measurements of GTPase activity and confocal imaging. These suggested a gain-of-function effect with increased GTPase activity and altered endoplasmatic reticulum morphology. The proposed disease mechanism is a transcript-specific heterozygous gain-of-function. Sources: Other |
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