CAG expansions in a novel gene for Machado-Joseph disease at chromosome 14q32.1

We have identified a novel gene containing CAG repeats and mapped it to chromosome 14q32.1, the genetic locus for Machado-Joseph disease (MJD). In normal individuals the gene contains between 13 and 36 CAG repeats, whereas most of the clinically diagnosed patients and all of the affected members of a family with the clinical and pathological diagnosis of MJD show expansion of the repeat-number (from 68–79). Southern blot analyses and genomic cloning demonstrates the existence of related genes. These results raise the possibility that similar abnormalities in related genes may give rise to diseases similar to MJD.

[1]  David E. Housman,et al.  Expansion of an unstable DNA region and phenotypic variation in myotonic dystrophy , 1992, Nature.

[2]  J. Weber,et al.  Chromosomal assignment of the second locus for autosomal dominant cerebellar ataxia (SCA2) to chromosome 12q23–24.1 , 1993, Nature Genetics.

[3]  Huda Y. Zoghbi,et al.  Expansion of an unstable trinucleotide CAG repeat in spinocerebellar ataxia type 1 , 1993, Nature Genetics.

[4]  A. Jauch,et al.  Detection of 14q32 translocations in B-cell malignancies by in situ hybridization with yeast artificial chromosome clones containing the human IgH gene locus. , 1994, Blood.

[5]  R. Albin,et al.  Widespread expression of the human and rat Huntington's disease gene in brain and nonneural tissues , 1993, Nature Genetics.

[6]  M. Ohta,et al.  Joseph disease in a non‐Portuguese family , 1983, Neurology.

[7]  R. Rosenberg.  Machado‐Joseph disease: An autosomal dominant motor system degeneration , 1992, Movement disorders : official journal of the Movement Disorder Society.

[8]  C. Mathew,et al.  Blot hybridisation analysis of genomic DNA. , 1984, Journal of medical genetics.

[9]  S. Nakanishi,et al.  Molecular cloning and chromosomal localization of the key subunit of the human N-methyl-D-aspartate receptor. , 1993, The Journal of biological chemistry.

[10]  J. Brust,et al.  Presumably Azorean disease in a presumably non‐Portuguese family , 1980, Neurology.

[11]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[12]  I. Verma,et al.  IκBγ, a 70 kd protein identical to the C-terminal half of p110 NF-κB: A new member of the IκB family , 1992, Cell.

[13]  O. Onodera,et al.  Unstable expansion of CAG repeat in hereditary dentatorubral–pallidoluysian atrophy (DRPLA) , 1994, Nature Genetics.

[14]  K. Fischbeck,et al.  Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy , 1991, Nature.

[15]  K. Nakano,et al.  Machado disease , 1972, Neurology.

[16]  T. Hunter,et al.  A mouse cdc25 homolog is differentially and developmentally expressed. , 1992, Genes & development.

[17]  J. Riley,et al.  Structure and physical map of 64 variable segments in the 3′ 0.8–megabase region of the human immunoglobulin heavy–chain locus , 1993, Nature Genetics.

[18]  Y. Kagawa,et al.  The gene for Machado–Joseph disease maps to human chromosome 14q , 1993, Nature Genetics.

[19]  K. Umesono,et al.  Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARα with a novel putative transcription factor, PML , 1991, Cell.

[20]  N. Bharucha,et al.  Machado-Joseph-Azorean disease in India. , 1986, Archives of neurology.

[21]  J. Haines,et al.  Machado-Joseph disease in pedigrees of Azorean descent is linked to chromosome 14. , 1994, American journal of human genetics.

[22]  G. Chazot,et al.  The natural history of Machado-Joseph disease: An analysis of 138 personally examined cases , 1984, Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques.

[23]  J. Penney,et al.  Trinucleotide repeat length instability and age of onset in Huntington's disease , 1993, Nature Genetics.

[24]  A. Sano,et al.  Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p , 1994, Nature Genetics.

[25]  Manish S. Shah,et al.  A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes , 1993, Cell.

[26]  David E. Housman,et al.  Molecular basis of myotonic dystrophy: Expansion of a trinucleotide (CTG) repeat at the 3′ end of a transcript encoding a protein kinase family member , 1992, Cell.

[27]  K. Davies,et al.  Trinucleotide repeat amplification and hypermethylation of a CpG island in FRAXE mental retardation , 1993, Cell.

[28]  A. Jauch,et al.  Characterization of two marker chromosomes in a patient with acute nonlymphocytic leukemia by two-color fluorescence in situ hybridization. , 1993, Cancer genetics and cytogenetics.

[29]  M. Hayden,et al.  The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease , 1993, Nature Genetics.

[30]  J. Sutcliffe,et al.  Variation of the CGG repeat at the fragile X site results in genetic instability: Resolution of the Sherman paradox , 1991, Cell.

[31]  P. Jong,et al.  Detection of an unstable fragment of DNA specific to individuals with myotonic dystrophy , 1992, Nature.

[32]  T. Ashizawa,et al.  An unstable triplet repeat in a gene related to myotonic muscular dystrophy. , 1992, Science.

[33]  G. Mckhann,et al.  Machado-Joseph disease in a Sicilian-American family. , 1986, Journal of neurogenetics.

[34]  C. Amemiya,et al.  Cloning of the essential myotonic dystrophy region and mapping of the putative defect , 1992, Nature.

[35]  E. Ohmura,et al.  Effects of chlorpromazine and naloxone on growth hormone secretion in rats. , 1980, Neuroendocrinology.

[36]  C. Amemiya,et al.  Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. , 1992, Science.

[37]  P. Coutinho,et al.  Clinical criteria for diagnosis of Machado‐Joseph disease , 1980, Neurology.

[38]  M. MacDonald,et al.  Relationship between trinucleotide repeat expansion and phenotypic variation in Huntington's disease , 1993, Nature Genetics.