PRICKLE1 – Epilepsy

PRICKLE1 variants have been implicated in early-onset epilepsy through both recessive and de novo mechanisms. Homozygous missense mutations were originally reported in three consanguineous families, and a novel de novo missense variant, c.1444G>A (p.Asp482Asn), was identified in a 7-year-old with epilepsy, autism spectrum disorder and global developmental delay (PMID:29790814). Across these four unrelated probands, no additional familial segregation beyond parental genotypes has been described, and all reported alleles are missense, suggesting a possible dominant-negative or gain-of-function effect.

Functional studies support a role for PRICKLE1 in neuronal excitability and synaptic vesicle regulation. Prickle1(+/–) mice and Drosophila models exhibit seizure-like behaviors and synaptic defects, and cell-based assays demonstrate disrupted PRICKLE1–SYNAPSIN I interaction leading to altered dense-core vesicle size ([PMID:24312498]). While these data concordantly link PRICKLE1 dysfunction to neuronal hyperexcitability, evidence is restricted to isolated families and models, warranting further replication in larger cohorts.

Key Take-home: PRICKLE1 missense variants in four unrelated patients with epilepsy show concordant functional abnormalities, but limited segregation data presently categorize this association as Limited; targeted testing may be considered in early-onset epilepsy after exclusion of common causes.

References

• Journal of neurogenetics • 2018 • A de novo mutation in PRICKLE1 associated with myoclonic epilepsy and autism spectrum disorder. PMID:29790814
• PloS one • 2013 • PRICKLE1 interaction with SYNAPSIN I reveals a role in autism spectrum disorders. PMID:24312498

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