PRKRA – Dystonia 16

DYT16 (Dystonia 16) is an autosomal recessive early-onset dystonia-parkinsonism caused by biallelic mutations in PRKRA, which encodes the PKR activator PACT (PMID:22842711). Patients present with generalized dystonia or dystonia-parkinsonism non-responsive to levodopa and refractory to pharmacological therapy.

Genetic analyses identified six homozygous carriers from Brazilian families exhibiting two phenotypes: generalized dystonia and dystonia-parkinsonism (PMID:22842711). In a cohort of 153 unrelated idiopathic dystonia patients, seven probands harbored PRKRA variants, including a novel c.795C>A (p.Ser265Arg) in compound heterozygosity with c.665C>T (p.Pro222Leu) (PMID:29279192). A Polish family study confirmed segregation of c.665C>T (p.Pro222Leu) in two siblings with early-onset generalized dystonia and mild parkinsonism (PMID:25142429).

The variant spectrum in DYT16 is dominated by missense changes; c.665C>T (p.Pro222Leu) recurs across populations. No biallelic loss-of-function variants have been reported. PRKRA mutations account for ~4.5% of isolated dystonia in the Brazilian cohort (PMID:29279192).

Functional studies demonstrate that PACT p.Pro222Leu enhances PACT-PACT and PACT-PKR interactions, leading to prolonged PKR activation, increased eIF2α phosphorylation and apoptosis in patient lymphoblasts (PMID:26231208). Truncated frameshift mutants aggregate in cells, triggering caspase-dependent apoptosis.

In the Prkralear-5J mouse model, homozygous frameshift mutants exhibit progressive dystonia, cerebellar Purkinje neuron dendritic arborization defects, and reduced eIF2α phosphorylation, recapitulating human DYT16 features (PMID:39512178).

Overall, multiple unrelated probands, segregation in a European pedigree, and concordant functional and animal model data support a Strong gene-disease association. Genetic testing for PRKRA variants is recommended in early-onset generalized dystonia to guide diagnosis and management.

References

• Journal of neurology, neurosurgery, and psychiatry • 2012 • DYT16: the original cases. PMID:22842711
• Parkinsonism & related disorders • 2018 • The prevalence of PRKRA mutations in idiopathic dystonia. PMID:29279192
• Movement disorders : official journal of the Movement Disorder Society • 2014 • DYT16 revisited: exome sequencing identifies PRKRA mutations in a European dystonia family. PMID:25142429
• The Journal of biological chemistry • 2015 • Altered activation of protein kinase PKR and enhanced apoptosis in dystonia cells carrying a mutation in PKR activator protein PACT. PMID:26231208
• Disease Models & Mechanisms • 2024 • Mutation in Prkra results in cerebellar abnormality and reduced eIF2α phosphorylation in a model of DYT-PRKRA. PMID:39512178

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