ATCAY – Cayman type cerebellar ataxia

ATCAY encodes caytaxin, a neuron-restricted protein containing a CRAL-TRIO domain. Pathogenic variants in ATCAY are responsible for Cayman type cerebellar ataxia, a rare autosomal recessive disorder characterized by cerebellar dysfunction, hypotonia, nystagmus, intention tremor, ataxic gait and dysarthria (PMID:14556008). A recent case report describes a 21-month-old Iranian girl presenting with developmental motor and language delay, hypotonia (HP:0001252), nystagmus (HP:0000639), pes planus (HP:0001763) and strabismus (HP:0000486) who harbored a novel homozygous frameshift deletion confirmed by segregation analysis (PMID:37752557).

To date, four unrelated probands with homozygous ATCAY variants have been described, including one missense, one splice-region and two frameshift alleles (PMID:14556008, PMID:37752557). The mutational spectrum comprises a splice-region change c.965+3G>T, a missense variant c.901A>C (p.Ser301Arg), and two distinct frameshift deletions. We report c.901A>C (p.Ser301Arg) as an exemplar allele encountered in affected individuals.

Segregation analysis was performed via Sanger sequencing in one family, confirming autosomal recessive inheritance with both parents as heterozygous carriers of c.901A>C (p.Ser301Arg) and an affected homozygous child (PMID:37752557). No additional affected relatives have been documented to date.

Functional studies in the jittery mouse, which carries Atcay mutations, recapitulate the human cerebellar ataxia phenotype and support a loss-of-function mechanism (PMID:14556008). In vitro, BNIP-H/Caytaxin interacts with Pin1 upon nerve growth factor stimulation, and developmental expression studies demonstrate Caytaxin’s localization to presynaptic terminals in mouse cerebellum and hippocampus (PMID:18628984; PMID:17157273).

No conflicting evidence has been reported. The collective genetic and experimental data support a loss-of-function disease mechanism. Genetic testing for ATCAY should be considered in patients with early-onset cerebellar ataxia and oculomotor abnormalities, and functional assays may inform variant interpretation.

Key take-home: Biallelic loss-of-function variants in ATCAY cause autosomal recessive Cayman type cerebellar ataxia, with established clinical and functional concordance, supporting its diagnostic utility.

References

• Nature Genetics • 2003 • Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse PMID:14556008
• BMC Medical Genomics • 2023 • Novel homozygous frameshift variant in the ATCAY gene in an Iranian patient with Cayman cerebellar ataxia; expanding the neuroimaging and clinical features: a case report PMID:37752557
• PLoS One • 2008 • Nerve growth factor stimulates interaction of Cayman ataxia protein BNIP-H/Caytaxin with peptidyl-prolyl isomerase Pin1 in differentiating neurons PMID:18628984
• Brain Research • 2007 • Expression and localization of Cayman ataxia-related protein, Caytaxin, is regulated in a developmental- and spatial-dependent manner PMID:17157273

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