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2004 Fiscal Year Final Research Report Summary

Molecular analysis of a new type of spinocerebellar degeneration with GFAP mutations

Research Project

Project/Area Number 15590902
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Neurology
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

NAKAGAWA Masanori  Kyoto Prefectural University of Medicine, Department of Neurology, Professor, 医学研究科, 教授 (50198040)

Project Period (FY) 2003 – 2004
KeywordsGFAP / Alexander disease / Genotype / phenotype correlation / Juvenile onset / Adult onset / mitochondrial DNA / Spinal cord atrophy / Ataxia
Research Abstract

Glial fibrillary acidic protein (GFAP) is an intermediate filament protein expressed in astrocyte. Recently heterozygous point mutations in the GFAP have been reported in patients with various forms of Alexander disease (ALX). ALX is classified into infantile, juvenile and adult forms by age of disease onset. Infantile form is characterized by progressive psychomotor deterioration, seizure, hydrocephalus, and dies in infancy. Juvenile form is characterized by psychomotor deterioration, bulbar signs, and weakness and spasticity of lower limbs, but mental retardation and progression are less severe than those of the infantile form. Adult form is characterized by ataxia, palatal myoclonus and spastic paraparesis, but the symptoms are extremely variable from severe neurological defects to asymptomatic state.
We reported familial cases of palatal myoclonus and spinal cord atrophy with V87G GFAP mutation. We also reported a new case of palatal myoclonus, pyramidal tract signs, cerebellar sign … More s, and marked atrophy of the medulla oblongata and spinal cord, and heterozygous R416W mutation which was also found in both of infantile and juvenile forms. To clarify the correlation of the clinical phenotypes and GFAP mutations, we analyzed nine patients in four Japanese families and reviewed 65 reported patients on the point of GFAP mutations. In addition, we produced the mutant GFAP expression vectors and investigated the expression pattern of the mutant GFAP in the culture cells.
In the 74 patients, 42, 13 and 19 patients were infantile, juvenile and adult forms, respectively. In the 19 patients with adult form, two of them had no subjective symptoms and six of seven families had family history of the disease. The juvenile and adult forms coexisted in the same family members. Palatal myoclonus was recognized only four patients with the adult form. Regarding MRI findings, frontal dominant white matter lesion was detected in the infantile form, but spinal cord atrophy was prominent in the adult form. The sites of GFAP mutation mainly localized at exon 1, 4 and 8. R416W mutation was detected all forms of ALX and no clear correlation between the clinical forms and nature of the mutations. Mitochondrial abnormalities, ragged-red fibers, mtDNA A8291G substitution and 9bp deletion, were detected in one patient with the juvenile form. No nestin mutation was detected in the adult form.
We produced four different GFAP mutations (T235C, T274G, C276T, C1260T) by site specific mutagenesis. These mutants were transfected into cloned human glioma cells. We investigated the expressions properties of the GFAP protein through immunohistochemical staining using anti-GFAP antibody. Over expression of GFAP was found in the cells with GFAP mutations in comparison with those of wild type GFAP.
In conclusion, we confirmed the phenotypic and genetic features of adult form ALX with GFAP mutations. The phenotypic difference between each form of ALX is due not only to the different site and nature of mutations in GFAP, but also to other modifying factor(s) like other intermediate filaments and mitochondrial functions. Comparison of the expression patterns of each mutation in transgenic mice and culture system may clarify the phenotypic and genetic correlation in ALX with GFAP mutations. Less

  • Research Products

    (23 results)

All 2004 2003

All Journal Article (23 results)

  • [Journal Article] Early pathological changes in the parkinsonian brain demonstrated by diffusion tensor MRI2004

    • Author(s)
      Yoshikawa K, Nakata Y, Nakagawa M, et al.
    • Journal Title

      J Neurol Neurosurg Psychiatry 75

      Pages: 481-484

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] SBF2/MTMR13 mutation causes CMT4B with juvenile onset glaucoma2004

    • Author(s)
      Hirano R, Takashima H, Nakagawa M, et al.
    • Journal Title

      Neurology 63

      Pages: 577-580

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Do white matter changes have clinical significance in Alzheimer's disease?2004

    • Author(s)
      Kono I, Mori S, Nakajima K, Nakagawa M, et al.
    • Journal Title

      Gerontology 50

      Pages: 242-246

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Juvenile form Alexander disease with GFAP mutation and mitochondrial abnormality2004

    • Author(s)
      Nobuhara Y, Nakahara K, Nakagawa M, et al.
    • Journal Title

      Neurology 63

      Pages: 1302-1304

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] White Matter Loss in the Splenium of the Corpus callosum in a Case of Posterior Cortical Atrophy : A Diffusion Tensor Imaging Study2004

    • Author(s)
      Yoshida T, Shiga K, Nakagawa M, et al.
    • Journal Title

      European Neurology 52

      Pages: 77-81

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Fine mapping of 16q-linked autosomal dominant cerebellar ataxia type III in Japanese families2004

    • Author(s)
      Hirano R, Takashima H, Nakagawa M, et al.
    • Journal Title

      Neurogenetics 5

      Pages: 215-221

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] 遺伝性ニューロパチーupdate2004

    • Author(s)
      中川正法, 高嶋 博
    • Journal Title

      臨床神経学 44

      Pages: 991-994

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Juvenile form Alexander disease with GFAP mutation and mitochondrial abnormality.2004

    • Author(s)
      Nobuhara Y, Nakahara K, Higuchi I, Yoshida T, Fushiki S, Osame M, Arimura K, Nakagawa M.
    • Journal Title

      Neurology 63

      Pages: 1302-1304

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Early pathological changes in the parkinsonian brain demonstrated by diffusion tensor MRI.2004

    • Author(s)
      Yoshikawa K, Nakata Y, Yamada K, Nakagawa M.
    • Journal Title

      J Neurol Neurosurg Psychiatry. 75

      Pages: 481-484

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] SBF2/MTMR13 mutation causes CMT4B with juvenile onset glaucoma.2004

    • Author(s)
      Hirano R, Takashima H, Umehara F, Arimura H, Michizono K, Okamoto Y, Nakagawa M, Boerkoel CF, Lupski JR, Osame M, Arimura K.
    • Journal Title

      Neurology 63

      Pages: 577-580

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Do white matter changes have clinical significance in Alzheimer's disease?2004

    • Author(s)
      Kono I, Mori S, Nakajima K, Nakagawa M, Watanabe Y, Kizu O, Yamada K, Sakai Y.
    • Journal Title

      Gerontology. 50

      Pages: 242-246

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] White Matter Loss in the Splenium of the Corpus callosum in a Case of Posterior Cortical Atrophy : A Diffusion Tensor Imaging Study.2004

    • Author(s)
      Yoshida T, Shiga K, Yoshikawa K, Yamada K, Nakagawa M.
    • Journal Title

      Eur Neurol 52

      Pages: 77-81

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Fine mapping of 16q-linked autosomal dominant cerebellar ataxia type III in Japanese families.2004

    • Author(s)
      Hirano R, Takashima H, Okubo R, Tajima K, Okamoto Y, Ishida S, Tsuruta K, Arisato T, Arata H, Nakagawa M, Osame M, Arimura K.
    • Journal Title

      Neurogenetics 5

      Pages: 215-221

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] A case of adult-onset Alexander disease with Arg416Trp human glial fibrillary acidic protein gene mutation2003

    • Author(s)
      Kinoshita T, Imaizumi T, Nakagawa M, et al.
    • Journal Title

      Neuroscience Letters 350

      Pages: 169-172

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Clinical and pathological studies of familial amyotrophic lateral sclerosis (FALS) with SOD1 H46R mutation in large Japanese families2003

    • Author(s)
      Arisato T, Okubo R, Nakagawa M, et al.
    • Journal Title

      Acta Neuropathologica 106

      Pages: 561-568

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Gap junction protein beta 1 (GJB1) mutations and central nervous system symptoms in X-linked Charcot-Marie-Tooth disease2003

    • Author(s)
      Takashima H, Nakagawa M, et al.
    • Journal Title

      Acta Neurologica Scandinavica 107

      Pages: 31-37

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] CMT4A : Identification of a Hispanic GDAP1 founder mutation2003

    • Author(s)
      Boerkoel CF, Takashima H, Nakagawa M, et al.
    • Journal Title

      Annals of Neurology 53

      Pages: 400-405

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Mitochondrial DNA mutation correlates with stage progression and prognosis in non-small cell lung cancer2003

    • Author(s)
      Matsuyama W, Nakagawa M, et al.
    • Journal Title

      Human mutation 21

      Pages: 441-443

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A case of adult-onset Alexander disease with Arg416Trp human glial fibrillary acidic protein gene mutation.2003

    • Author(s)
      Kinoshita T, Imaizumi T, Miura Y, Fujimoto H, Ayabe M, Shoji H, Okamoto Y, Takashima H, Osame M, Nakagawa M.
    • Journal Title

      Neuroscience Letters 350

      Pages: 169-172

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Clinical and pathological studies of familial amyotrophic lateral sclerosis (FALS) with SOD1 H46R mutation in large Japanese families.2003

    • Author(s)
      Arisato T, Okubo R, Arata H, Abe K, Fukada K, Saburo Sakoda S, Akira Simizu A, QH Xing, Izumo S, Osame M, Nakagawa M.
    • Journal Title

      Acta Neuropathologica 106

      Pages: 561-568

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Gap junction protein beta 1 (GJB1) mutations and central nervous system symptoms in X-linked Charcot-Marie-Tooth disease.2003

    • Author(s)
      Takashima H, Nakagawa M, Umehara F, Hirata K, Suehara M, Mayumi H, Yoshishige K, Matsuyama W, Saito M, Jonosono M, Arimura K, Osame, M.
    • Journal Title

      Acta Neurol Scand 107

      Pages: 31-37

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] CMT4A : Identification of a Hispanic GDAP1 founder mutation.2003

    • Author(s)
      Boerkoel CF, Takashima H, Nakagawa M, Izumo S, Armstrong D, Butler I, Mancias P, Papasozomenos SC, Stern LZ, Lupski JR.
    • Journal Title

      Ann.Neurol 53

      Pages: 400-405

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Mitochondrial DNA mutation correlates with stage progression and prognosis in non-small cell lung cancer.2003

    • Author(s)
      Matsuyama W, Nakagawa M, Wakimoto J, Hirotsu Y, Kawabata M, Osame M.
    • Journal Title

      Human mutation 21

      Pages: 441-443

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2006-07-11  

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