Glial fibrillary acidic protein mutations in infantile, juvenile, and adult forms of Alexander disease

Alexander disease is a progressive, usually fatal neurological disorder defined by the widespread and abundant presence in astrocytes of protein aggregates called Rosenthal fibers. The disease most often occurs in infants younger than 2 years and has been labeled a leukodystrophy because of an accompanying severe myelin deficit in the frontal lobes. Later onset forms have also been recognized based on the presence of abundant Rosenthal fibers. In these cases, clinical signs and pathology can be quite different from the infantile form, raising the question whether they share the same underlying cause. Recently, we and others have found pathogenic, de novo missense mutations in the glial fibrillary acidic protein gene in most infantile patients examined and in a few later onset patients. To obtain further information about the role of glial fibrillary acidic protein mutations in Alexander disease, we analyzed 41 new patients and another 3 previously described clinically, including 18 later onset patients. Our results show that dominant missense glial fibrillary acidic protein mutations account for nearly all forms of this disorder. They also significantly expand the catalog of responsible mutations, verify the value of magnetic resonance imaging diagnosis, indicate an unexpected male predominance for the juvenile form, and provide insights into phenotype–genotype relations. Ann Neurol 2005;57:310–326

[1]  E. Lane,et al.  Identification of two novel mutations in keratin 13 as the cause of white sponge naevus. , 2008, Oral diseases.

[2]  F. Barkhof,et al.  Unusual variants of Alexander's disease , 2005, Annals of neurology.

[3]  M. Brenner,et al.  Dominantly‐inherited adult‐onset leukodystrophy with palatal tremor caused by a mutation in the glial fibrillary acidic protein gene , 2004, Movement disorders : official journal of the Movement Disorder Society.

[4]  M. Nakagawa,et al.  A case of adult-onset Alexander disease with Arg416Trp human glial fibrillary acidic protein gene mutation , 2003, Neuroscience Letters.

[5]  A. Bassuk,et al.  Alexander disease with serial MRS and a new mutation in the glial fibrillary acidic protein gene , 2003, Neurology.

[6]  F. Hanefeld,et al.  A Novel GFAP Mutation and Disseminated White Matter Lesions: Adult Alexander Disease? , 2003, European Neurology.

[7]  J. Montplaisir,et al.  Adult Alexander disease with autosomal dominant transmission: a distinct entity caused by mutation in the glial fibrillary acid protein gene. , 2003, Archives of neurology.

[8]  M. Brenner,et al.  Alexander's Disease , 2003, Journal of child neurology.

[9]  Hans Scheffer,et al.  Mutation analysis of the entire keratin 5 and 14 genes in patients with epidermolysis bullosa simplex and identification of novel mutations , 2003, Human mutation.

[10]  M. Indelman,et al.  Epidermolysis bullosa simplex in Israel: clinical and genetic features. , 2003, Archives of dermatology.

[11]  C. Kraus,et al.  Diagnosesicherung des Morbus Alexander in vivo durch Mutationsanalyse des GFAP-Gens , 2003, Monatsschrift Kinderheilkunde.

[12]  Ueli Aebi,et al.  Molecular architecture of intermediate filaments , 2003, BioEssays : news and reviews in molecular, cellular and developmental biology.

[13]  S. Tsujino,et al.  Molecular genetic study in Japanese patients with Alexander disease: a novel mutation, R79L , 2003, Brain and Development.

[14]  H. Zeumer,et al.  Atypical focal MRI lesions in a case of juvenile Alexander's disease , 2003, Annals of neurology.

[15]  H. Shimazaki,et al.  Identification of GFAP gene mutation in hereditary adult‐onset Alexander's disease , 2002, Annals of neurology.

[16]  H. Hoshi,et al.  MR imaging and 1H-MR spectroscopy in a case of juvenile Alexander disease , 2002, Brain and Development.

[17]  U. Stephani,et al.  Infantile Alexander disease: a GFAP mutation in monozygotic twins and novel mutations in two other patients. , 2002, Neuropediatrics.

[18]  J. Goldman,et al.  GFAP mutations in Alexander disease , 2002, International Journal of Developmental Neuroscience.

[19]  E. Hoffman,et al.  Molecular findings in symptomatic and pre-symptomatic Alexander disease patients , 2002, Neurology.

[20]  G. Takada,et al.  Juvenile Alexander disease with a novel mutation in glial fibrillary acidic protein gene. , 2002, Neurology.

[21]  Shu-fen Lee,et al.  Novel KRT14 mutation in a Taiwanese patient with epidermolysis bullosa simplex (Köbner type). , 2002, Journal of the Formosan Medical Association = Taiwan yi zhi.

[22]  K. Arimura,et al.  Autosomal dominant palatal myoclonus and spinal cord atrophy , 2002, Journal of the Neurological Sciences.

[23]  T. Shiihara,et al.  Fluctuation of Computed Tomographic Findings in White Matter in Alexander's Disease , 2002, Journal of child neurology.

[24]  E. Bertini,et al.  Infantile Alexander disease: spectrum of GFAP mutations and genotype-phenotype correlation. , 2001, American journal of human genetics.

[25]  D. Murrell,et al.  Keratin 14 point mutations at codon 119 of helix 1A resulting in different epidermolysis bullosa simplex phenotypes. , 2001, The Journal of investigative dermatology.

[26]  Y. Matsubara,et al.  A novel mutation in glial fibrillary acidic protein gene in a patient with Alexander disease , 2001, Neuroscience Letters.

[27]  S. Tsujino,et al.  Diagnosis of Alexander disease in a Japanese patient by molecular genetic analysis , 2001, Journal of Human Genetics.

[28]  J. McGrath,et al.  New mutations in keratin 1 that cause bullous congenital ichthyosiform erythroderma and keratin 2e that cause ichthyosis bullosa of Siemens , 2001, The British journal of dermatology.

[29]  S. Antonarakis,et al.  Nomenclature for the description of human sequence variations , 2001, Human Genetics.

[30]  J. Goldman,et al.  Alexander Disease: New Insights From Genetics , 2001, Journal of neuropathology and experimental neurology.

[31]  M. Akiyama,et al.  A novel leucine to valine mutation in residue 7 of the helix initiation motif of keratin10 leads to bullous congenital ichthyosiform erythroderma. , 2001, The Journal of investigative dermatology.

[32]  C. Brenner Genomic approaches to elucidation of the Fhit pathway in worms and yeast: Rosetta Stone and synthetic lethals , 2001, Nature Genetics.

[33]  J. Valk,et al.  Alexander disease: diagnosis with MR imaging. , 2001, AJNR. American journal of neuroradiology.

[34]  R. Schmidt,et al.  Effect of NGF and Neurotrophin‐3 Treatment on Experimental Diabetic Autonomic Neuropathy , 2001, Journal of neuropathology and experimental neurology.

[35]  G. Melino,et al.  A Novel Mutation in the Keratin 13 Gene Causing Oral White Sponge Nevus , 2001, Journal of dental research.

[36]  D. Parry,et al.  Coiled-coil trigger motifs in the 1B and 2B rod domain segments are required for the stability of keratin intermediate filaments. , 2000, Molecular biology of the cell.

[37]  M. Nachman,et al.  Estimate of the mutation rate per nucleotide in humans. , 2000, Genetics.

[38]  J. Uitto,et al.  Novel keratin 16 mutations and protein expression studies in pachyonychia congenita type 1 and focal palmoplantar keratoderma , 2000, Experimental dermatology.

[39]  H. Scheffer,et al.  Exempting homologous pseudogene sequences from polymerase chain reaction amplification allows genomic keratin 14 hotspot mutation analysis. , 2000, The Journal of investigative dermatology.

[40]  E. Tanzi,et al.  Mutation report: identification of a germline mutation in keratin 17 in a family with pachyonychia congenita type 2. , 1999, The Journal of investigative dermatology.

[41]  D. Parry,et al.  Identification of novel mutations in basic hair keratins hHb1 and hHb6 in monilethrix: implications for protein structure and clinical phenotype. , 1999, The Journal of investigative dermatology.

[42]  J. Primrose,et al.  Optimisation of DNA and RNA extraction from archival formalin-fixed tissue. , 1999, Nucleic acids research.

[43]  J. Bodensteiner,et al.  Alexander's Disease: Unique Presentation , 1999, Journal of child neurology.

[44]  D. Hohl,et al.  An asparagine to threonine substitution in the 1A domain of keratin 1: a novel mutation that causes epidermolytic hyperkeratosis , 1999, Experimental dermatology.

[45]  J. Uitto,et al.  A mutation detection strategy for the human keratin 6A gene and novel missense mutations in two cases of pachyonychia congenita type 1 , 1999, Experimental dermatology.

[46]  J. Martín,et al.  Infantile and juvenile presentations of Alexander's disease: a report of two cases , 1999, Acta neurologica Scandinavica.

[47]  L. Bolund,et al.  Identification of novel and known mutations in the genes for keratin 5 and 14 in Danish patients with epidermolysis bullosa simplex: correlation between genotype and phenotype. , 1999, The Journal of investigative dermatology.

[48]  D. Parry,et al.  Molecular Parameters of Type IV α-Internexin and Type IV-Type III α-Internexin-Vimentin Copolymer Intermediate Filaments* , 1999, The Journal of Biological Chemistry.

[49]  J. Uitto,et al.  Mutations in keratin K9 in kindreds with epidermolytic palmoplantar keratoderma and epidemiology in Northern Ireland. , 1998, The Journal of investigative dermatology.

[50]  E. Lane,et al.  Genomic organization and fine mapping of the keratin 2e gene (KRT2E): K2e V1 domain polymorphism and novel mutations in ichthyosis bullosa of Siemens. , 1998, The Journal of investigative dermatology.

[51]  A. Quantock,et al.  Isolation and chromosomal localization of a cornea-specific human keratin 12 gene and detection of four mutations in Meesmann corneal epithelial dystrophy. , 1997, American journal of human genetics.

[52]  H. Shinkai,et al.  A novel mutation of a leucine residue in coil 1A of keratin 9 in epidermolytic palmoplantar keratoderma. , 1997, The Journal of investigative dermatology.

[53]  G. Sharpe,et al.  A new keratin 2e mutation in ichthyosis bullosa of Siemens. , 1997, The Journal of investigative dermatology.

[54]  E. Lane,et al.  Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex. , 1997, The Journal of investigative dermatology.

[55]  H. Scheffer,et al.  Effects of keratin 14 ablation on the clinical and cellular phenotype in a kindred with recessive epidermolysis bullosa simplex. , 1996, The Journal of investigative dermatology.

[56]  H. Shimizu,et al.  A novel keratin K5 gene mutation in Dowling-Meara epidermolysis bullosa simplex. , 1996, The Journal of investigative dermatology.

[57]  M. Inagaki,et al.  Detection of protein kinase activity specifically activated at metaphase-anaphase transition , 1996, The Journal of cell biology.

[58]  D. Kelsell,et al.  Novel mutations in keratin 16 gene underly focal non-epidermolytic palmoplantar keratoderma (NEPPK) in two families. , 1995, Human molecular genetics.

[59]  J. Bonifas,et al.  Keratin 14 gene mutations in patients with epidermolysis bullosa simplex. , 1995, The Journal of investigative dermatology.

[60]  E. Lane,et al.  Keratin 16 and keratin 17 mutations cause pachyonychia congenita , 1995, Nature Genetics.

[61]  E. Fuchs,et al.  Genetic and clinical mosaicism in a type of epidermal nevus. , 1994, The New England journal of medicine.

[62]  E. Lane,et al.  A functional "knockout" of human keratin 14. , 1994, Genes & development.

[63]  P. Fritsch,et al.  Mutations of keratin 9 in two families with palmoplantar epidermolytic hyperkeratosis. , 1994, The Journal of investigative dermatology.

[64]  K. Yamanishi,et al.  A novel mutation of Leu122 to Phe at a highly conserved hydrophobic residue in the helix initiation motif of keratin 14 in epidermolysis bullosa simplex. , 1994, Human Molecular Genetics.

[65]  H. Hennies,et al.  Keratin 9 gene mutational heterogeneity in patients with epidermolytic palmoplantar keratoderma , 1994, Human Genetics.

[66]  E. Fuchs,et al.  Genetic mutations in the K1 and K10 genes of patients with epidermolytic hyperkeratosis. Correlation between location and disease severity. , 1994, The Journal of clinical investigation.

[67]  Karl Sperling,et al.  Keratin 9 gene mutations in epidermolytic palmoplantar keratoderma (EPPK) , 1994, Nature Genetics.

[68]  S. Bale,et al.  Preferential sites in keratin 10 that are mutated in epidermolytic hyperkeratosis. , 1994, American journal of human genetics.

[69]  Y. Sakaki,et al.  Alpha B-crystallin and 27-kd heat shock protein are regulated by stress conditions in the central nervous system and accumulate in Rosenthal fibers. , 1993, The American journal of pathology.

[70]  D Hohl,et al.  Mutations in the Rod Domains of Keratins 1 and 10 in Epidermolytic Hyperkeratosis , 1992, Science.

[71]  T. Iwaki,et al.  Rosenthal fibers share epitopes with alpha B-crystallin, glial fibrillary acidic protein, and ubiquitin, but not with vimentin. Immunoelectron microscopy with colloidal gold. , 1991, The American journal of pathology.

[72]  C. Croce,et al.  Human glial fibrillary acidic protein: complementary DNA cloning, chromosome localization, and messenger RNA expression in human glioma cell lines of various phenotypes. , 1991, Cancer research.

[73]  M. Dohadwala,et al.  Characterization of human cDNA and genomic clones for glial fibrillary acidic protein. , 1990, Brain research. Molecular brain research.

[74]  A. Johnson,et al.  On-grid immunogold labeling of glial intermediate filaments in epoxy-embedded tissue. , 1989, The American journal of anatomy.

[75]  T. Iwaki,et al.  αB-crystallin is expressed in non-lenticular tissues and accumulates in Alexander's disease brain , 1989, Cell.

[76]  R. Chalkley,et al.  The separation of transcriptionally engaged genes. , 1988, The Journal of biological chemistry.

[77]  David N. Cooper,et al.  The CpG dinucleotide and human genetic disease , 1988, Human Genetics.

[78]  L. Chen,et al.  Absence of Intermediate Filaments in a Human Adrenal Cortex Carcinoma‐Derived Cell Line a , 1985, Experimental cell research.

[79]  M. Solomon,et al.  Formaldehyde-mediated DNA-protein crosslinking: a probe for in vivo chromatin structures. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[80]  A. Aron,et al.  Alexander's disease , 1976, Neurology.

[81]  W. Schlote [Piloid astrocytes (spongiocytes) and Rosenthal fibers in multiple sclerosis (author's transl)]. , 1975, Acta Neuropathologica.

[82]  W. Schlote Piloide Astrocyten (Spongiocyten) und Rosenthalsche Fasern bei multipler Sklerose , 1975, Acta Neuropathologica.

[83]  P. Yates,et al.  Rosenthal fibres in tumours of the central nervous system , 1957 .

[84]  W. S. Alexander Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. , 1949, Brain : a journal of neurology.

[85]  D. Rodriguez,et al.  Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease , 2001, Nature Genetics.

[86]  J. Uitto,et al.  Molecular genetics of Meesmann's corneal dystrophy: ancestral and novel mutations in keratin 12 (K12) and complete sequence of the human KRT12 gene. , 2000, Experimental eye research.

[87]  M. Akiyama,et al.  A novel asparagine-->aspartic acid mutation in the rod 1A domain in keratin 2e in a Japanese family with ichthyosis bullosa of Siemens. , 2000, The Journal of investigative dermatology.

[88]  E. Fuchs,et al.  The cytoskeleton and disease: genetic disorders of intermediate filaments. , 1996, Annual review of genetics.

[89]  S. Bale,et al.  Mutations in the H1 and 1A domains in the keratin 1 gene in epidermolytic hyperkeratosis. , 1994, The Journal of investigative dermatology.

[90]  G. Lenoir,et al.  Epidermolytic palmoplantar keratoderma cosegregates with a keratin 9 mutation in a pedigree with breast and ovarian cancer , 1994, Nature Genetics.

[91]  J. Uitto,et al.  Identification of a leucine‐to‐proline mutation in the keratin 5 gene in a family with the generalized Köbner type of epidermolysis bullosa simplex , 1993, Human mutation.

[92]  友兼 尚之 Rosenthal fibers shares epitopes with αβ-crystallin, glial fibrillary acidic protein, and ubiquitin, but not with vimentin : Immunoelectron microscopy with colloidal gold , 1991 .

[93]  T. Iwaki,et al.  Alpha B-crystallin is expressed in non-lenticular tissues and accumulates in Alexander's disease brain. , 1989, Cell.