Abstract
Background:Huntington’s disease (HD) is a progressive neurodegenerative condition that causes degeneration of neurons in the brain, ultimately leading to death. The root cause of HD is an expanded trinucleotide cytosine-adenine-guanine (CAG) repeat in the “huntingtin gene” (HTT). While there is a rough correlation between the number of CAG repeats and disease onset, the development of clinical symptoms can vary by decades within individuals and little is known about this pre-symptomatic phase.Methods:Using peripheral blood samples from HD patients and healthy controls we usedEpiSwitch™, a validated high-resolution industrial platform for the detection of chromosome conformations, to assess chromatin architecture in the immediate vicinity of theHTTgene. We evaluated chromatin conformations at 20 sites across 225 kb of theHTTlocus in healthy controls, verified symptomatic HD patients (CAG, n>39) and patients with CAG expansions who had not yet manifested clinical symptoms of HD.Results:Discrete chromosome conformations were observed across the patient groups. We found two constitutive interactions (occurring in all patient groups) and seven conditional interactions which were present in HD, but not in healthy controls. Most important, we observed three conditional interactions that were present only in HD patients manifesting clinical symptoms (symptomatic cases), but not in presymptomatic cases. Of the patients in the symptomatic HD cohort, 86% (6 out of 7) demonstrated at least one of the specific chromosome conformations associated with symptomatic HD.Conclusion:Our results provide the first evidence that chromatin architecture at theHTTlocus is systemically altered in patients with HD, with conditional differences between clinical stages. Given the high clinical need in having a molecular tool to assess disease progression in HD, these results strongly suggest that the non-invasive assessment of chromosome conformation signatures can be a valuable addition to prognostic assessment of HD patients.
Highlights
Huntington’s disease (HD) is a neurodegenerative condition characterized cellularly by the loss of neurons in the basal ganglia and clinically by uncontrolled movements, emotional problems, and loss of cognition[1]
We identified a set of seven interactions that when taken together as a chromosome conformation signature (CCS), could differentiate HD from unaffected controls and more importantly, could differentiate between presymptomatic and symptomatic HD patients
Biological relevance While it is known that the poly-Q repeat tract expansion and production of mutant huntingtin protein (mHTT) are the underlying causes of HD, the molecular events leading to the development of clinical symptoms are less well characterized
Summary
Huntington’s disease (HD) is a neurodegenerative condition characterized cellularly by the loss of neurons in the basal ganglia and clinically by uncontrolled movements, emotional problems, and loss of cognition[1]. In patients with mid-range repeat lengths (defined here as between 40 and 50), disease onset can vary by 60 years in any individual patient[5]. This means that many patients who are carriers of polyQ tracts that predispose to the development of the disease can live for decades in a “presymptomatic” state[7]. While there is a rough correlation between the number of CAG repeats and disease onset, the development of clinical symptoms can vary by decades within individuals and little is known about this pre-symptomatic phase.
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