title: The HTT CAG-Expansion Mutation Determines Age at Death but Not Disease Duration in Huntington Disease.
abstract: Huntington disease (HD) is caused by an expanded HTT CAG repeat that leads in a length-dependent, completely dominant manner to onset of a characteristic movement disorder. HD also displays early mortality, so we tested whether the expanded CAG repeat exerts a dominant influence on age at death and on the duration of clinical disease. We found that, as with clinical onset, HD age at death is determined by expanded CAG-repeat length and has no contribution from the normal CAG allele. Surprisingly, disease duration is independent of the mutation's length. It is also unaffected by a strong genetic modifier of HD motor onset. These findings suggest two parsimonious alternatives. (1) HD pathogenesis is driven by mutant huntingtin, but before or near motor onset, sufficient CAG-driven damage occurs to permit CAG-independent processes and then lead to eventual death. In this scenario, some pathological changes and their clinical correlates could still worsen in a CAG-driven manner after disease onset, but these CAG-related progressive changes do not themselves determine duration. Alternatively, (2) HD pathogenesis is driven by mutant huntingtin acting in a CAG-dependent manner with different time courses in multiple cell types, and the cellular targets that lead to motor onset and death are different and independent. In this scenario, processes driven by HTT CAG length lead directly to death but not via the striatal pathology associated with motor manifestations. Each scenario has important ramifications for the design and testing of potential therapeutics, especially those aimed at preventing or delaying characteristic motor manifestations.
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Jae Whan
authors: JW
authors: Keum
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Aram
authors: A
authors: Shin
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Tammy
authors: T
authors: Gillis
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Jayalakshmi Srinidhi
authors: JS
authors: Mysore
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Kawther
authors: K
authors: Abu Elneel
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Diane
authors: D
authors: Lucente
authors: GNS Healthcare Inc., One Charles Park, Cambridge, MA 02142, USA.
authors: Tiffany
authors: T
authors: Hadzi
authors: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK; Genetic Modifiers of Huntington's Disease Consortium.
authors: Peter
authors: P
authors: Holmans
authors: Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff CF24 4HQ, UK; Genetic Modifiers of Huntington's Disease Consortium.
authors: Lesley
authors: L
authors: Jones
authors: Department of Neurology, University of Ulm, Ulm 089081, Germany; Genetic Modifiers of Huntington's Disease Consortium.
authors: Michael
authors: M
authors: Orth
authors: CHDI Foundation, Princeton, NJ 08540, USA; Genetic Modifiers of Huntington's Disease Consortium.
authors: Seung
authors: S
authors: Kwak
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Genetic Modifiers of Huntington's Disease Consortium.
authors: Marcy E
authors: ME
authors: MacDonald
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Genetic Modifiers of Huntington's Disease Consortium.
authors: James F
authors: JF
authors: Gusella
authors: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Medical and Population Genetics Program, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Genetic Modifiers of Huntington's Disease Consortium. Electronic address: jlee51@mgh.harvard.edu.
authors: Jong-Min
authors: JM
authors: Lee
mesh_terms: D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003342:Corpus Striatum / Q000378:metabolism; D006239:Haplotypes; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D055815:Young Adult
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins