A homozygous mutation in human PRICKLE1 causes an autosomal-recessive progressive myoclonus epilepsy-ataxia syndrome.
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.
Bassuk
Alexander G
AG
Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
Wallace
Robyn H
RH
Buhr
Aimee
A
Buller
Andrew R
AR
Afawi
Zaid
Z
Shimojo
Masahito
M
Miyata
Shingo
S
Chen
Shan
S
Gonzalez-Alegre
Pedro
P
Griesbach
Hilary L
HL
Wu
Shu
S
Nashelsky
Marcus
M
Vladar
Eszter K
EK
Antic
Dragana
D
Ferguson
Polly J
PJ
Cirak
Sebahattin
S
Voit
Thomas
T
Scott
Matthew P
MP
Axelrod
Jeffrey D
JD
Gurnett
Christina
C
Daoud
Azhar S
AS
Kivity
Sara
S
Neufeld
Miriam Y
MY
Mazarib
Aziz
A
Straussberg
Rachel
R
Walid
Simri
S
Korczyn
Amos D
AD
Slusarski
Diane C
DC
Berkovic
Samuel F
SF
El-Shanti
Hatem I
HI
D000595:Amino Acid Sequence; D001259:Ataxia / Q000235:genetics*; D002881:Chromosomes, Human, Pair 12; D003241:Consanguinity; D005808:Genes, Recessive; D005819:Genetic Markers; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D060588:LIM Domain Proteins; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D020191:Myoclonic Epilepsies, Progressive / Q000235:genetics*; D010375:Pedigree; D020161:Physical Chromosome Mapping; D013577:Syndrome; D025521:Tumor Suppressor Proteins / Q000235:genetics*
D005819:Genetic Markers; D060588:LIM Domain Proteins; C515173:PRICKLE1 protein, human; D025521:Tumor Suppressor Proteins