Genetic modifiers of somatic expansion and clinical phenotypes in Huntington’s disease reveal shared and tissue-specific effects
Author:
, Lee Jong-MinORCID, McLean Zachariah L., Correia Kevin, Shin Jun Wan, Lee Sujin, Jang Jae-Hyun, Lee Yukyeong, Kim Kyung-Hee, Choi Doo Eun, Long Jeffrey D., Lucente Diane, Seong Ihn Sik, Pinto Ricardo MouroORCID, Giordano James V., Mysore Jayalakshmi S., Siciliano Jacqueline, Elezi Emanuela, Ruliera Jayla, Gillis Tammy, Wheeler Vanessa C.ORCID, MacDonald Marcy E., Gusella James F., Gatseva Anna, Ciosi Marc, Lomeikaite Vilija, Loay Hossameldin, Monckton Darren G.ORCID, Wills Christopher, Massey Thomas H., Jones Lesley, Holmans PeterORCID, Kwak Seung, Sampaio CristinaORCID, Orth Michael, Bernhard Landwehrmeyer G., Paulsen Jane S., Ray Dorsey E., Myers Richard H.
Abstract
ABSTRACTHuntington’s disease (HD), due to expansion of a CAG repeat inHTT, is representative of a growing number of disorders involving somatically unstable short tandem repeats. We find that overlapping and distinct genetic modifiers of clinical landmarks and somatic expansion in blood DNA reveal an underlying complexity and cell-type specificity to the mismatch repair-related processes that influence disease timing. Differential capture of non-DNA-repair gene modifiers by multiple measures of cognitive and motor dysfunction argues additionally for cell-type specificity of pathogenic processes. Beyondtransmodifiers, differential effects are also illustrated atHTTby a 5’-UTR variant that promotes somatic expansion in blood without influencing clinical HD, while, even after correcting for uninterrupted CAG length, a synonymous sequence change at the end of the CAG repeat dramatically hastens onset of motor signs without increasing somatic expansion. Our findings are directly relevant to therapeutic suppression of somatic expansion in HD and related disorders and provide a route to define the individual neuronal cell types that contribute to different HD clinical phenotypes.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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