A Universal Mechanism Ties Genotype to Phenotype in Trinucleotide Diseases

Trinucleotide hereditary diseases such as Huntington disease and Friedreich ataxia are cureless diseases associated with inheriting an abnormally large number of DNA trinucleotide repeats in a gene. The genes associated with different diseases are unrelated and harbor a trinucleotide repeat in different functional regions; therefore, it is striking that many of these diseases have similar correlations between their genotype, namely the number of inherited repeats and age of onset and progression phenotype. These correlations remain unexplained despite more than a decade of research. Although mechanisms have been proposed for several trinucleotide diseases, none of the proposals, being disease-specific, can account for the commonalities among these diseases. Here, we propose a universal mechanism in which length-dependent somatic repeat expansion occurs during the patient's lifetime toward a pathological threshold. Our mechanism uniformly explains for the first time to our knowledge the genotype–phenotype correlations common to trinucleotide disease and is well-supported by both experimental and clinical data. In addition, mathematical analysis of the mechanism provides simple explanations to a wide range of phenomena such as the exponential decrease of the age-of-onset curve, similar onset but faster progression in patients with Huntington disease with homozygous versus heterozygous mutation, and correlation of age of onset with length of the short allele but not with the long allele in Friedreich ataxia. If our proposed universal mechanism proves to be the core component of the actual mechanisms of specific trinucleotide diseases, it would open the search for a uniform treatment for all these diseases, possibly by delaying the somatic expansion process.

[1]  R. Albin,et al.  Neurological abnormalities in a knock-in mouse model of Huntington's disease. , 2001, Human molecular genetics.

[2]  L. Noble,et al.  Microsatellites — Evolution and Applications , 1999, Heredity.

[3]  O. Combarros,et al.  GAA expansion size and age at onset of Friedreich’s ataxia , 2003, Neurology.

[4]  O. Combarros,et al.  Expanded GAA repeats and clinical variation in Friedreich's ataxia , 2004, Acta neurologica Scandinavica.

[5]  James F. Gusella,et al.  Molecular genetics: Unmasking polyglutamine triggers in neurodegenerative disease , 2000, Nature Reviews Neuroscience.

[6]  H. Kawakami,et al.  The effect of CAT trinucleotide interruptions on the age at onset of spinocerebellar ataxia type 1 (SCA1) , 1999, Journal of medical genetics.

[7]  F. Squitieri,et al.  CAG mutation effect on rate of progression in Huntington's disease , 2002, Neurological Sciences.

[8]  H. Zoghbi,et al.  Evidence for a mechanism predisposing to intergenerational CAG repeat instability in spinocerebellar ataxia type I , 1993, Nature Genetics.

[9]  P. Shelbourne,et al.  Dramatic mutation instability in HD mouse striatum: does polyglutamine load contribute to cell-specific vulnerability in Huntington's disease? , 2000, Human molecular genetics.

[10]  B Brinkmann,et al.  Mutation rate in human microsatellites: influence of the structure and length of the tandem repeat. , 1998, American journal of human genetics.

[11]  Y. Agid,et al.  Molecular and clinical correlations in autosomal dominant cerebellar ataxia with progressive macular dystrophy (SCA7). , 1998, Human molecular genetics.

[12]  D. Rubinsztein Lessons from animal models of Huntington's disease. , 2002, Trends in genetics : TIG.

[13]  Osamu Onodera,et al.  SCA17 homozygote showing Huntington's disease‐like phenotype , 2004, Annals of neurology.

[14]  F. Squitieri,et al.  New Huntington disease mutation arising from a paternal CAG34 allele showing somatic length variation in serially passaged lymphoblasts , 2005, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[15]  N W Wood,et al.  Trinucleotide repeats and neurodegenerative disease. , 2004, Brain : a journal of neurology.

[16]  Osamu Onodera,et al.  Trinucleotide repeat length and rate of progression of Huntington's disease , 1994, Annals of neurology.

[17]  Joonil Jung,et al.  CREB-Binding Protein Modulates Repeat Instability in a Drosophila Model for PolyQ Disease , 2007, Science.

[18]  J. Walcott,et al.  Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice. , 2001, Human molecular genetics.

[19]  F. Squitieri,et al.  Highly disabling cerebellar presentation in Huntington disease , 2003, European journal of neurology.

[20]  J. Brandt,et al.  The association of CAG repeat length with clinical progression in Huntington disease , 2006, Neurology.

[21]  A. Ciarmiello,et al.  The search for cerebral biomarkers of Huntington's disease: a review of genetic models of age at onset prediction , 2006, European journal of neurology.

[22]  D. Rubinsztein,et al.  A molecular investigation of true dominance in Huntington’s disease , 1999, Journal of medical genetics.

[23]  S. A. Ross,et al.  A linear lattice model for polyglutamine in CAG-expansion diseases , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[24]  G. Bates History of genetic disease: The molecular genetics of Huntington disease — a history , 2005, Nature Reviews Genetics.

[25]  S. Choudhry,et al.  CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms. , 2001, Human molecular genetics.

[26]  Huda Y. Zoghbi,et al.  Diseases of Unstable Repeat Expansion: Mechanisms and Common Principles , 2005, Nature Reviews Genetics.

[27]  L. Ranum,et al.  Pathogenic RNA repeats: an expanding role in genetic disease. , 2004, Trends in genetics : TIG.

[28]  L. Pianese,et al.  Determinants of onset age in Friedreich’s ataxia , 1998, Journal of Neurology.

[29]  Shin Kwak,et al.  FRIEDREICH'S ATAXIA , 1917, Nihon rinsho. Japanese journal of clinical medicine.

[30]  Elizabeth Evans,et al.  Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. , 2003, Human molecular genetics.

[31]  C. E. Pearson,et al.  Repeat instability: mechanisms of dynamic mutations , 2005, Nature Reviews Genetics.

[32]  M. Siciliano,et al.  Dramatic, expansion-biased, age-dependent, tissue-specific somatic mosaicism in a transgenic mouse model of triplet repeat instability. , 2000, Human molecular genetics.

[33]  C J Lumsden,et al.  Inherited neurodegenerative diseases: the one-hit model of neurodegeneration. , 2001, Human molecular genetics.

[34]  M. Hayden,et al.  The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. , 1997, American journal of human genetics.

[35]  Thorsten Schmidt,et al.  Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis , 2004, The Lancet Neurology.

[36]  F. Giubilei,et al.  Natural history of cardiac involvement in myotonic dystrophy: Correlation with CTG repeats , 2000, Neurology.

[37]  A. Messer,et al.  Msh2 deficiency prevents in vivo somatic instability of the CAG repeat in Huntington disease transgenic mice , 1999, Nature Genetics.

[38]  K. Fischbeck,et al.  Androgen receptor mutation in Kennedy's disease. , 1999, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[39]  M. F. Perutz,et al.  Cause of neural death in neurodegenerative diseases attributable to expansion of glutamine repeats , 2001, Nature.

[40]  M. Hayden,et al.  Homozygosity for CAG mutation in Huntington disease is associated with a more severe clinical course. , 2003, Brain : a journal of neurology.