Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population

Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India.
Journal of Human Genetics (Impact Factor: 2.46). 02/2005; 50(7):347-52. DOI: 10.1007/s10038-005-0263-7
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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.

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Available from: Shinichi Hirose, Oct 04, 2015
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    • "Lafora disease (LD) is a rare form of inherited progressive myoclonus epilepsy (OMIM#254780; ORPHA501). Recessive mutations in either the EPM2A gene encoding a dual-specificity phosphatase known as laforin (OMIM 607566) (Minassian et al., 1998; Serratosa et al., 1999) or in the EPM2B/NHLRC1 gene encoding malin (OMIM 608072), an E3 ubiquitin ligase (Chan et al., 2003; Gentry et al., 2005; Gomez-Abad et al., 2005; Singh et al., 2005, 2006) are responsible for the disease, although the existence of a third, minor locus has also been postulated (Chan et al., 2004). "
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    ABSTRACT: Lafora disease is a rare form of inherited progressive myoclonus epilepsy caused by mutations in the EPM2A gene encoding laforin, or in the EPM2B gene, which encodes malin. It is characterized by the presence of polyglucosan inclusion bodies (Lafora bodies) in brain and other tissues. Genetically engineered mice lacking expression of either the laforin (Epm2a(-/-) ) or malin (Epm2b(-/-) ) genes display a number of neurological and behavioral abnormalities that resemble those found in patients suffering from Lafora disease; of these, both Epm2a(-/-) and Epm2b(-/-) mice have shown altered motor activity, impaired motor coordination, episodic memory deficits, and different degrees of spontaneous epileptic activity. In this study, we analyze the sensitivity of Epm2a(-/-) and Epm2b(-/-) mice to the convulsant drug pentylenetetrazol (PTZ), an antagonist of the γ-aminobutyric acid type A (GABAA) receptor, commonly used to induce epileptic tonic-clonic seizures in laboratory animals. PTZ-induced epileptic activity, including myoclonic jerks and tonic-clonic seizures, was analyzed in 2 age groups of mice comprising representative samples of young adult and aged mice, after administration of PTZ at sub-convulsive and convulsive doses. Epm2a(-/-) and Epm2b(-/-) mice showed a lower convulsive threshold after PTZ injections at sub-convulsive doses. A lower convulsive threshold and shorter latencies to develop epileptic seizures were observed after PTZ injections at convulsive doses. Different patterns of generalized seizures and of discharges were observed in Epm2a(-/-) and Epm2b(-/-) mice. Epm2a(-/-) and Epm2b(-/-) mice present an increased sensitivity to the convulsant agent PTZ that may reflect different degrees of increased GABAA receptor-mediated hyperexcitability.
    Frontiers in Neuroscience 09/2014; 8:291. DOI:10.3389/fnins.2014.00291 · 3.66 Impact Factor
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    • "Two peaks are the result of a duplex PCR. PCR of 156 bp represents the control PCR used for normalization and the other is region of the NHLRC1 gene amplified with LD2L4R4 primers [9]. Below the peak, the first number is the length of PCR product in base pairs (bp), and the second is the area of the peaks. "
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    ABSTRACT: Lafora disease (LD) is a severe, autosomal recessive, latechildhood- to teenage-onset, progressive myoclonic epilepsy. It is due to either EPM2A or NHLRC1 mutations. We describe a patient with homozygous deletion encompassing the entire NHLRC1 gene, not previously reported, and with clinical course more progressive than in the most patients with NHLRC1 mutations. The diagnosis of LD in our patient was based on the typical clinic, neurophysiological presentation, as well as skin biopsy followed by molecular genetics findings. She developed normally until the age of 15, when she had her first occipital and generalized seizures. Four years after the first seizure the patient became bedridden, demented and presented with severe clinical condition. She died of pneumonia at age 20. This report is the first case of homozygosity for NHLRC1 deletion and thus adds to mutational heterogeneity of LD. Besides, it widens the spectrum of LD patients with severe phenotype and NHLRC1 mutations.
    Journal of the neurological sciences 01/2013; 325(1-2). DOI:10.1016/j.jns.2012.12.006 · 2.47 Impact Factor
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    • "LD has been well described in the Mediterranean basin, the Middle East and Asian countries, and North America, and mutations in NHLRC1 are generally more common than in EPM2A [11–14, 19, 20]. Patients have been reported in Africa [15–17]; however, the diagnosis was based on skin biopsy, which may have false positive results [21, 22]. "
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    ABSTRACT: We studied a Malian family with parental consanguinity and two of eight siblings affected with late-childhood-onset progressive myoclonus epilepsy and cognitive decline, consistent with the diagnosis of Lafora disease. Genetic analysis showed a novel homozygous single-nucleotide variant in the NHLRC1 gene, c.560A>C, producing the missense change H187P. The changed amino acid is highly conserved, and the mutation impairs malin's ability to degrade laforin in vitro. Pathological evaluation showed manifestations of Lafora disease in the entire brain, with particularly severe involvement of the pallidum, thalamus, and cerebellum. Our findings document Lafora disease with severe manifestations in the West African population. Electronic supplementary material The online version of this article (doi:10.1007/s10048-009-0190-4) contains supplementary material, which is available to authorized users.
    Neurogenetics 04/2009; 10(4):319-23. DOI:10.1007/s10048-009-0190-4 · 2.88 Impact Factor
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