Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population.
Lafora disease (LD) is a rare autosomal recessive genetic disorder characterized by epilepsy, myoclonus, and progressive neurological deterioration. LD is caused by mutations in the EMP2A gene encoding a protein phosphatase. A second gene for LD, termed NHLRC1 and encoding a putative E3 ubiquitin ligase, was recently identified on chromosome 6p22. The LD is relatively common in southern Europe, the Middle East, and Southeast Asia. A few sporadic cases with typical LD phenotype have been reported from Japan; however, our earlier study failed to find EPM2A mutations in four Japanese families with LD. We recruited four new families from Japan and searched for mutations in EPM2A . All eight families were also screened for NHLRC1 mutations. We found five independent families having novel mutations in NHLRC1. Identified mutations include five missense mutations (p.I153M, p.C160R, p.W219R, p.D245N, and p.R253K) and a deletion mutation (c.897insA; p.S299fs13). We also found a family with a ten base pair deletion (c.822-832del10) in the coding region of EPM2A. In two families, no EPM2A or NHLRC1 mutation was found. Our study, in addition to documenting the genetic and molecular heterogeneity observed for LD, suggests that mutations in the NHLRC1 gene may be a common cause of LD in the Japanese population.
Singh
Shweta
S
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
Suzuki
Toshimitsu
T
Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1, Hirosawa, Wako, Saitama 351-0198, Japan.
Uchiyama
Akira
A
Tokyo Metropolitan Medical Center for Severely Handicapped, Tokyo, Japan.
Kumada
Satoko
S
Tokyo Metropolitan Medical Center for Severely Handicapped, Tokyo, Japan.
Moriyama
Nobuko
N
National Rehabilitation Center for Disabled Children, Tokyo, Japan.
Hirose
Shinichi
S
Department of Pediatrics, School of Medicine, Fukuoka University, Fukuoka, Japan.
Takahashi
Yukitoshi
Y
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorder, Shizuoka, Japan.
Sugie
Hideo
H
Department of Pediatric Neurology, Hamamatsu City Medical Center for Developmental Medicine, Shizuoka, Japan.
Mizoguchi
Koichi
K
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorder, Shizuoka, Japan.
Inoue
Yushi
Y
National Epilepsy Center, Shizuoka Institute of Epilepsy and Neurological Disorder, Shizuoka, Japan.
Kimura
Kazue
K
Segawa Neurological Clinic for Children, Tokyo, Japan.
Sawaishi
Yukio
Y
Department of Reproductive and Developmental Medicine, Division of Pediatrics, Akita University School of Medicine, Akita, Japan.
Yamakawa
Kazuhiro
K
Laboratory for Neurogenetics, RIKEN Brain Science Institute, 2-1, Hirosawa, Wako, Saitama 351-0198, Japan. yamakawa@brain.riken.jp.
Ganesh
Subramaniam
S
Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D017931:DNA Primers; D040461:Gene Components; D005820:Genetic Testing; D006801:Humans; D007564:Japan / Q000453:epidemiology; D020192:Lafora Disease / Q000453:epidemiology* / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases
D002352:Carrier Proteins; D017931:DNA Primers; C478960:NHLRC1 protein, human; D044767:Ubiquitin-Protein Ligases; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human