Z Argov

Hadassah Medical Center, Yerushalayim, Jerusalem District, Israel

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Publications (95)514.66 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: GNE myopathy is a recessive adult onset, slowly progressive distal and proximal myopathy, caused by mutations in the GNE gene. The most frequent mutation in GNE myopathy patients is the Middle Eastern founder mutation M712T. We have generated Gne ( M712T/M712T ) knockin mice. A high mortality rate in the first generation due to renal failure was recorded (as previously described). However, the following Gne ( M712T/M712T ) offspring generations could be classified into 3 phenotypic categories: severe, mild and without apparent phenotype. By further crossing between mice with no apparent phenotype, we were able to establish a colony of Gne ( M712T/M712T ) knockin mice with a high- and long-term survival rate, lacking any renal phenotype. These mice did not present any muscle phenotype (clinical or pathological) for up to 18 months. No correlation was found between the expression of any of the two mRNA Gne isoforms in muscle and the mouse genotype or phenotype. However, the expression of isoform 2 mRNA was significantly higher in the kidney of Gne ( M712T/M712T ) kidney affected mice compared with control. In contrast, the expression of UPR markers Bip, Chop and of the spliced form of XBP1, was upregulated in muscle of Gne ( M712T/M712T ) mice compared with controls, but was unchanged in the affected kidney. Thus, Gne defects can affect both muscle and kidney in mouse, but probably through different mechanisms.
    Neuromolecular medicine 12/2012; 15(1). · 5.00 Impact Factor
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    ABSTRACT: We present further developments in the study of the antisense oligonucleotide EN101. Ongoing in vitro and in vivo studies demonstrate that EN101 is a TLR9-specific ligand that can suppress pro-inflammatory functions and shift nuclear factor kappa B (NF-κB) from the pro-inflammatory canonical pathway to the anti-inflammatory alternative pathway, which results in decreases acetylcholinesterase (AChE) activity. Preliminary results of a double-blinded phase II cross-over study compared 10, 20, and 40 mg EN101 administered to patients with myasthenia gravis. Patients were randomly assigned to one of three treatment groups in weeks 1, 3, and 5 and received their pretreatment dose of pyridostigmine in weeks 2 and 4. Thus far, all doses show a decrease in QMG scores, with a greater response to higher doses.
    Annals of the New York Academy of Sciences 12/2012; 1275(1):13-6. · 4.38 Impact Factor
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    ABSTRACT: GNE myopathy is an autosomal recessive adult onset disorder caused by mutations in the GNE gene. GNE encodes the bifunctional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetyl mannosamine kinase, the key enzyme in the biosynthesis pathway of sialic acid. Additional functions for GNE have been described recently, but the mechanism leading from GNE mutation to this myopathy is unclear. Therefore a gene therapy approach could address all potential defects caused by GNE mutations in muscle. We show that AAV8 viral vectors carrying wild type human GNE cDNA are able to transduce murine muscle cells and human GNE myopathy-derived muscle cells in culture and to express the transgene in these cells. Furthermore, the intravenous administration of this viral vector to healthy mice allows expression of the GNE transgene mRNA and of the coexpressed luciferase protein, for at least 6months in skeletal muscles, with no clinical or pathological signs of focal or general toxicity, neither from the virus particles nor from the wild type human GNE overexpression. Our results support the future use of an AAV8 based vector platform for a safe and efficient therapy of muscle in GNE myopathy.
    Neuromuscular Disorders 05/2012; · 3.13 Impact Factor
  • Neuromuscular Disorders 10/2011; 21(9):718-718. · 3.13 Impact Factor
  • Neuromuscular Disorders 10/2011; 21(9):718-718. · 3.13 Impact Factor
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    ABSTRACT: Acetylcholinesterase pre-mRNA is susceptible to alternative splicing. Myasthenia gravis has been shown to be associated with the expression of the readthrough transcript (AChE-R), which, unlike the normal "synaptic" transcript (AChE-S) is not tethered to the post-synaptic membrane, but is a soluble monomer in the synaptic cleft. In rats with experimental autoimmune myasthenia gravis (EAMG), inhibition of production of AChE-R using antisense is associated with a significant reduction in synaptic expression of AChE-R mRNA and protein, with improved muscle strength and stamina and increased survival. Synaptic AChE does not appear to be significantly affected by the induction of EAMG or treatment with antisense to AChE-R. Monarsen (EN101) is a synthetic 20-base antisense oligodeoxynucleotide directed against the human AChE gene. It is modified to achieve stability for oral administration. Sixteen patients with seropositive myasthenia gravis who were responsive to pyridostigmine were withdrawn from it and treated with Monarsen. Fourteen patients experienced a clinically significant response. In some, the improvement was dramatic. Although the dose of pyridostigmine was not optimized before the study, the majority of responders achieved better Quantitative Myasthenia Gravis scores than on pyridostigmine. The response of an individual muscle group to Monarsen was related to the degree of deterioration following the withdrawal of pyridostigmine. Cholinergic side effects were conspicuous by their absence. Monarsen is now being investigated in a phase II study.
    Annals of the New York Academy of Sciences 07/2008; 1132:283-90. · 4.31 Impact Factor
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    ABSTRACT: Charcot-Marie-Tooth type 1A (CMT1A) is an autosomal dominant polyneuropathy due to a 1.5 Mb tandem duplication in chromosome 17p11.2, containing the PMP22 gene. This mutation is not modified during inheritance. We set forth to test the hypothesis that in a subgroup of CMT1A patients there is clinical anticipation, namely an increase in disease severity over generations. Thirty-nine CMT1A mutation-positive patients in 16 families and 23 parent-offspring pairs were evaluated. This included 14 families with 2 generations and 2 families with 3 generations. Age of presentation was assessed by interviewing the patients and clinical severity was measured using the CMT neuropathy score (CMTNS). In 21/23 parent-child pairs and 14/16 families, there was an earlier age of presentation in children of genetically affected parents. The mean age of onset in the progeny was 12.61 years compared to 41.22 years in the parent generation, (p < 0.001). Mean severity in the younger generation was slightly higher than that of the parent generation. When corrected for the age difference, the trend for a worse phenotype in the younger generation became statistically significant (p < 0.02,Wilcoxon signed rank test). Our findings suggest that in a subgroup of CMT1A patients there is an increase in clinical severity over generations. The mechanism responsible for this observation remains unknown. Our findings should be validated on a larger cohort of CMT1A families.
    Journal of Neurology 04/2008; 255(6):813-9. · 3.84 Impact Factor
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    ABSTRACT: Dysferlin encoding gene (DYS) is mutated in the autosomal recessive disorders Miyoshi myopathy, Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and distal anterior compartment myopathy, causing dysferlin deficiency in muscle biopsy. Three ethnic clusters have previously been described in Dysferlinopathy: the Libyan Jewish population originating in the area of Tripoli, Italian and Spanish populations. We report another cluster of this muscular dystrophy in Israel among Jews of the Caucasus region. A genomic analysis of the dysferlin coding sequence performed in patients from this ethnic group, who demonstrated an absence of dysferlin expression in muscle biopsy, revealed a homozygous frameshift mutation of G deletion at codon 927 (2779delG) predicting a truncated protein and a complete loss of functional protein. The possible existence of a founder effect is strengthened by our finding of a 4% carrier frequency in this community. These findings are important for genetic counseling and also enable a molecular diagnosis of LGMD2B in Jews of the Caucasus region.
    Neuromuscular Disorders 01/2008; 17(11-12):950-4. · 3.13 Impact Factor
  • Neurology 09/2007; 69(7):699-700. · 8.30 Impact Factor
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    ABSTRACT: Mutations in GNE encoding UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) cause hereditary inclusion body myopathy (HIBM). To define the role of GNE mutations in HIBM pathogenesis, GNE protein expression was analyzed. GNE protein is expressed at equal levels in HIBM patients and normal control subjects. Immunofluorescence detection of GNE did not reveal any mislocalization of GNE in skeletal muscle. We conclude that impaired GNE function, not lack of expression, may be the key pathogenic factor in HIBM. For diagnostic purposes, direct genetic analysis of the GNE gene in patients with IBM will remain the mainstay and is not aided by immunohistochemistry or immunoblotting using antibodies against the GNE protein.
    Neurology 09/2007; 69(7):655-9. · 8.30 Impact Factor
  • Annals of the New York Academy of Sciences 12/2006; 508(1):448 - 450. · 4.38 Impact Factor
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    ABSTRACT: Recessively inherited hereditary inclusion body myopathy (HIBM) with quadriceps sparing was initially described only in Jews originating from the region of Persia. The recent identification of the gene responsible for this myopathy and the common "Persian Jewish mutation" (M712T) enabled the re-evaluation of atypical phenotypes and the epidemiology of HIBM in various communities in the Middle East. To test for the M712T mutation in the DNA from HIBM patients in the Middle East. DNA from all suspected HIBM patients was tested for the M712T mutation. Unaffected members of families with genetically proven HIBM were studied too. In the majority of families, haplotype construction with markers spanning the 700-kb region of the HIBM gene was performed. One hundred twenty-nine HIBM patients of 55 families (Middle Eastern Jews, Karaites, and Arab Muslims of Palestinian and Bedouin origin) were homozygous for the M712T mutation, and all carried the same haplotype. Five clinically unaffected subjects were also homozygous for the common mutation and haplotype, including two older adults (ages 50 and 68 years). Atypical features with this same mutation were marked quadriceps weakness in five patients, proximal weakness only in two patients, facial weakness in three patients, and a muscle biopsy showing perivascular inflammation in one patient. The phenotypic spectrum of recessive HIBM is wider than previously described, and the diagnostic criteria for this myopathy must be changed. The Middle Eastern cluster is the result of a founder mutation, with incomplete penetrance, that is approximately 1,300 years old and is not limited to Jews.
    Neurology 06/2003; 60(9):1519-23. · 8.30 Impact Factor
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    ABSTRACT: The human RECK gene, mapped at 9p13-->p12, is known as a tumor suppressor gene and as a key regulator of extracellular matrix integrity and angiogenesis. We have established the entire genomic structure of this gene, which spans more than 87 kb and consists of 21 exons and 20 introns, and identified thirteen single nucleotide polymorphisms (SNPs). Four SNPs were identified in the coding region of the gene (exons 1, 9, 13 and 15), and the remaining nine in introns 5, 8, 10, 12, 15 and 17. The availability of the genomic organization of the RECK gene and the identification of polymorphisms throughout its entire genome will facilitate the evaluation of its role in several disorders and also contribute to the assignment of genes to the several diseases mapped to this chromosomal region.
    Cytogenetic and Genome Research 01/2002; 97(1-2):58-61. · 1.91 Impact Factor
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    ABSTRACT: Post-exercise recovery of intracellular pH (pH(i)) assessed using phosphorus magnetic resonance spectroscopy has not been previously evaluated in its entirety due to its complex time-course and missing data points resulting from a transient loss of inorganic phosphate signal. By considering the transition from exercise to recovery as a step function input, pH(i) recovery was modeled based on the creatine-kinase equilibrium, and the entire pH(i) recovery was characterized by calculating the time required for pH(i) recovery (t(pHrec)). Applying this methodology, normal subjects showed a strong linear correlation between phosphocreatine (PCr) half-time and t(pHrec) (r = 0.90, P < 0.001). In mitochondrial myopathy (MM) patients with weakness in the limb examined, 9/10 had faster pH(i) recovery relative to PCr recovery; wide normal ranges from a control group which included deconditioned subjects resulted in 7 of those 10 patients having otherwise normal recovery indices. Therefore, modeling pH(i) recovery allows characterization of the entire pH(i) recovery and detects altered proton handling in MM patients, including those with otherwise normal recovery indices.
    Magnetic Resonance in Medicine 12/2001; 46(5):870-8. · 3.40 Impact Factor
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    ABSTRACT: Hereditary inclusion body myopathy (HIBM; OMIM 600737) is a unique group of neuromuscular disorders characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. The autosomal recessive form described in Jews of Persian descent is the HIBM prototype. This myopathy affects mainly leg muscles, but with an unusual distribution that spares the quadriceps. This particular pattern of weakness distribution, termed quadriceps-sparing myopathy (QSM), was later found in Jews originating from other Middle Eastern countries as well as in non-Jews. We previously localized the gene causing HIBM in Middle Eastern Jews on chromosome 9p12-13 (ref. 5) within a genomic interval of about 700 kb (ref. 6). Haplotype analysis around the HIBM gene region of 104 affected people from 47 Middle Eastern families indicates one unique ancestral founder chromosome in this community. By contrast, single non-Jewish families from India, Georgia (USA) and the Bahamas, with QSM and linkage to the same 9p12-13 region, show three distinct haplotypes. After excluding other potential candidate genes, we eventually identified mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene in the HIBM families: all patients from Middle Eastern descent shared a single homozygous missense mutation, whereas distinct compound heterozygotes were identified in affected individuals of families of other ethnic origins. Our findings indicate that GNE is the gene responsible for recessive HIBM.
    Nature Genetics 10/2001; 29(1):83-7. · 29.65 Impact Factor
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    ABSTRACT: Hereditary inclusion body myopathy (HIBM) is a group of neuromuscular disorders characterised by adult-onset, slowly progressive distal and proximal muscle weakness and typical muscle pathology. Previously, we have mapped the gene responsible for a recessive form of HIBM to chromosome 9p1 and narrowed the interval to one single YAC clone of 1 Mb in size. As a further step towards the identification of the HIBM gene, we have constructed a detailed physical and transcriptional map of this region. A high resolution BAC contig that includes the HIBM critical region, flanked by marker 327GT4 and D9S1859, was constructed. This contig allowed the precise localisation of 25 genes and ESTs to the proximal region of chromosome 9. The expression pattern of those mapped genes and ESTs was established by Northern blot analysis. In the process of refining the HIBM interval, 13 new polymorphic markers were identified, of which 11 are CA-repeats, and two are single nucleotide polymorphisms. Certainly, this map provides an important integration of physical and transcriptional information corresponding to chromosome 9p12-p13, which is expected to facilitate the cloning and identification not only of the HIBM gene, but also other disease genes which map to this region.
    European Journal of HumanGenetics 08/2001; 9(7):501-9. · 4.23 Impact Factor
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    ABSTRACT: Dysferlin is the protein product of the gene (DYSF) that is defective in patients with limb girdle muscular dystrophy type 2B and Miyoshi myopathy. Calpain 3 is the muscle-specific member of the calcium activated neutral protease family and primary mutations in the CAPN3 gene cause limb girdle muscular dystrophy type 2A. The functions of both proteins remain speculative. Here we report a secondary reduction in calpain 3 expression in eight out of 16 patients with a primary dysferlinopathy and clinical features characteristic of limb girdle muscular dystrophy type 2B or Miyoshi myopathy. Previously CAPN3 analysis had been undertaken in three of these patients and two showed seemingly innocuous missense mutations, changing calpain 3 amino acids to those present in the sequences of calpains 1 and 2. These results suggest that there may be an association between dysferlin and calpain 3, and further analysis of both genes may elucidate a novel functional interaction. In addition, an association was found between prominent expression of smaller forms of the 80 kDa fragment of laminin alpha 2 chain (merosin) and dysferlin-deficiency.
    Neuromuscular Disorders 01/2001; 10(8):553-9. · 3.13 Impact Factor
  • Z Argov
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    ABSTRACT: Two major entities continue to be controversial in the field of clinical myotoxicity: the various myopathies that are induced by the cholesterol-lowering agents and the acute quadriplegic myopathy of intensive care. Both conditions are relatively common, but their pathogenesis is unclear. The problematic issues related to these disorders are presented, with suggested topics for future research.
    Current Opinion in Neurology 11/2000; 13(5):541-5. · 5.73 Impact Factor
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    ABSTRACT: Phosphorus magnetic resonance spectroscopy (P-MRS) has now been used in the investigation of muscle energy metabolism in health and disease for over 15 years. The present review describes the basics of the metabolic observations made by P-MRS including the assumptions and problems associated with the use of this technique. Extramuscular factors, which may affect the P-MRS results, are detailed. The important P-MRS observations in patients with mitochondrial myopathies, including the monitoring of experimental therapies, are emphasized. The findings in other metabolic myopathies (those associated with glycolytic defects or endocrine disturbances) and in the destructive myopathies (the dystrophies and the inflammatory myopathies) are also described. Observations made in normal and abnormal fatigue, fibromyalgia, and malignant hyperthermia are considered. Finally, a summary of the possible diagnostic use of P-MRS in exercise intolerance is provided.
    Muscle & Nerve 10/2000; 23(9):1316-34. · 2.31 Impact Factor
  • Neli Boneva, Talma Brenner, Zohar Argov
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    ABSTRACT: A patient with painful neuropathy developed ocular, facial, and masticatory weakness and fatigue after 3 months of gabapentin (GBP) treatment (400 mg/day). An elevated level of serum acetylcholine receptor antibodies (AChR-Ab) was detected. The patient recovered following pyridostigmine therapy and withdrawal of GBP and, 2 years later, is practically asymptomatic despite positive AChR-Ab. Because of this clinical observation, we gave 150 mg/kg GBP to rats with experimental autoimmune myasthenia gravis (EAMG). Repetitive nerve stimulation at 3-Hz was performed, and the 5th/1st amplitude ratio was used to calculate the decremental response. In all EAMG rats, GBP induced a transient, abnormal decrement (7-20%) 90 to 240 min after administration. No decrement was induced by GBP in normal rats. Thus, GBP aggravates the decrement in EAMG. The mechanism involved in the hitherto unreported possible unmasking of myasthenia gravis (MG) by GBP is unknown. Gabapentin should be used with caution in this disease.
    Muscle & Nerve 09/2000; 23(8):1204-8. · 2.31 Impact Factor

Publication Stats

2k Citations
514.66 Total Impact Points


  • 1990–2012
    • Hadassah Medical Center
      • Department of Neurology
      Yerushalayim, Jerusalem District, Israel
  • 1986–2008
    • Hebrew University of Jerusalem
      • • Department of Neurobiology
      • • Hadassah Medical School
      Yerushalayim, Jerusalem District, Israel
  • 1986–2006
    • University of Pennsylvania
      • • Department of Biochemistry and Biophysics
      • • Department of Medicine
      Philadelphia, PA, United States
  • 2000
    • University of Chicago
      • Department of Medicine
      Chicago, IL, United States
  • 1997–2000
    • Montreal Heart Institute
      Montréal, Quebec, Canada
  • 1999
    • McGill University
      • Department of Biomedical Engineering
      Montréal, Quebec, Canada
    • Université du Québec à Montréal
      Montréal, Quebec, Canada
    • The National Institute of Neurology and Neurosurgery
      Tlalpam, The Federal District, Mexico
  • 1986–1989
    • Hospital of the University of Pennsylvania
      • • Department of Biochemistry and Biophysics
      • • Department of Neurology
      Philadelphia, Pennsylvania, United States