A Homozygous Mutation in Human PRICKLE1 Causes an Autosomal-Recessive Progressive Myoclonus Epilepsy-Ataxia Syndrome

Abstract

Progressive myoclonus epilepsy (PME) is a syndrome characterized by myoclonic seizures (lightning-like jerks), generalized convulsive seizures, and varying degrees of neurological decline, especially ataxia and dementia. Previously, we characterized three pedigrees of individuals with PME and ataxia, where either clinical features or linkage mapping excluded known PME loci. This report identifies a mutation in PRICKLE1 (also known as RILP for REST/NRSF interacting LIM domain protein) in all three of these pedigrees. The identified PRICKLE1 mutation blocks the PRICKLE1 and REST interaction in vitro and disrupts the normal function of PRICKLE1 in an in vivo zebrafish overexpression system. PRICKLE1 is expressed in brain regions implicated in epilepsy and ataxia in mice and humans, and, to our knowledge, is the first molecule in the noncanonical WNT signaling pathway to be directly implicated in human epilepsy.

Zebrafish Prickle1b mediates facial branchiomotor neuron migration via a farnesylation-dependent nuclear activity

“…7A-B), suggesting that this mutation does not disrupt trafficking of Pk1b. This result precisely parallels the behavior of full-length human PK1 and PK1-R104Q in HeLa cells (Bassuk et al, 2008). However, we found that Venus-Pk1b-R125Q had a reduced capacity to rescue FBMN migration in Pk1b morphants, such that only 33.7% of Venus-positive neurons migrated to r5 and r6, whereas 66.3% of neurons remained in r4 (Fig.…”

“…Previous work in cell culture has established that PK1 can regulate the nuclear translocation of REST (Shimojo and Hersh, 2003;Bassuk et al, 2008). Bassuk et al identified a PK1 mutation in human patients with PME (Bassuk et al, 2008).…”

“…Bassuk et al identified a PK1 mutation in human patients with PME (Bassuk et al, 2008). This mutation, R104Q, lies in the PET domain of the protein, severely disrupts interaction with REST and compromises the ability of PK1 to mediate REST nuclear translocation.…”

“…Interaction with PK1 influences REST nuclear localization and therefore its repressive ability in cell culture (Shimojo and Hersh, 2003;Shimojo and Hersh, 2006;Bassuk et al, 2008). Recently, a mutation in PK1 that reduces binding to REST has been linked to the autosomal recessive syndrome progressive myoclonus epilepsy with ataxia (PME) (Bassuk et al, 2008). Although PK1 expression has been observed in several neuronal subtypes in human cortex and cerebellum, it is currently unclear how PK1 and/or REST function in vivo, and how their dysfunction might contribute to the PME syndrome.…”

“…REST plays numerous roles in many cell types, including repression of neuronal genes in non-neuronal cells and regulation of the terminal differentiation of neurons (reviewed by Ballas and Mandel, 2005;Qureshi and Mehler, 2009). Interaction with PK1 influences REST nuclear localization and therefore its repressive ability in cell culture (Shimojo and Hersh, 2003;Shimojo and Hersh, 2006;Bassuk et al, 2008). Recently, a mutation in PK1 that reduces binding to REST has been linked to the autosomal recessive syndrome progressive myoclonus epilepsy with ataxia (PME) (Bassuk et al, 2008).…”