ATCAY encodes for Caytaxin, a neuronally restricted protein that is expressed specifically in the hippocampus, cortex, cerebellum, and olfactory bulb (PMID: 17157273), where it recruits cholinergic machinery to neurite terminals to promote acetylcholine signaling and neuritogenesis (PMID: 26343454).
ATCAY was first reported in relation to Cayman Ataxia, due a high frequency of this disorder in a highly inbred area of Grand Cayman Island (PMID: 14556008). It is characterized by prominent cerebellar dysfunction (ataxia, nystagmus, intention tremor, dysarthria), psychomotor retardation, and cerebellar hypoplasia. Genomic variants in this gene have been reported outside of the Cayman Island (PMIDs: 29449188, 33624863), therefore, all phenotypes listed above have been grouped as one disease entity: Cerebellar ataxia (MONDO: 0000437).
Evidence supporting this gene-disease relationship includes case-level data and experimental evidence. Summary of Case Level Data: 8 POINTS. This curation has 2 non-sense variants and one splice site variant in 3 unrelated probands from 3 publications (PMIDs: 14556008, 29449188, 33624863 ). This gene-disease association is supported by mouse models harboring ATCAY variants (jittery, sidewinder) that display an early onset ataxia that can be rescued with the expression of wild type human caytaxin (PMID: 23226316).
In summary, there is DEFINITIVE evidence to support this gene-disease relationship. No convincing contradictory evidence has emerged. This classification was approved by the ClinGen Cerebral Palsy Gene Curation Expert Panel on 02/20/2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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