Abstract
Age of onset (AO) of Huntington disease (HD) is mainly determined by the length of the CAG repeat expansion (CAGexp) in exon 1 of the HTT gene. Additional genetic variation has been suggested to contribute to AO, although the mechanism by which it could affect AO is presently unknown. The aim of this study is to explore the contribution of candidate genetic factors to HD AO in order to gain insight into the pathogenic mechanisms underlying this disorder. For that purpose, two AO definitions were used: the earliest age with unequivocal signs of HD (earliest AO or eAO), and the first motor symptoms age (motor AO or mAO). Multiple linear regression analyses were performed between genetic variation within 20 candidate genes and eAO or mAO, using DNA and clinical information of 253 HD patients from REGISTRY project. Gene expression analyses were carried out by RT-qPCR with an independent sample of 35 HD patients from Basque Country Hospitals. We found suggestive association signals between HD eAO and/or mAO and genetic variation within the E2F2, ATF7IP, GRIN2A, GRIN2B, LINC01559, HIP1 and GRIK2 genes. Among them, the most significant was the association between eAO and rs2742976, mapping to the promoter region of E2F2 transcription factor. Furthermore, rs2742976 T allele patient carriers exhibited significantly lower lymphocyte E2F2 gene expression, suggesting a possible implication of E2F2-dependent transcriptional activity in HD pathogenesis. Thus, E2F2 emerges as a new potential HD AO modifier factor.
Highlights
Huntington’s disease (HD) (OMIM 143100) is a neurodegenerative disorder characterized by movement abnormalities, cognitive decline and psychiatric disturbances, which most often become noticeable between the ages of 35 and 50 [1]
The earliest AO (eAO) of the European Huntington’s Disease Network (EHDN) sample analyzed in this work ranged from 21 to 73 years
Age of onset in HD is inversely correlated with the CAG repeat length in the mutated Huntingtin protein (HTT) allele
Summary
Huntington’s disease (HD) (OMIM 143100) is a neurodegenerative disorder characterized by movement abnormalities (chorea, hypokinesia), cognitive decline and psychiatric disturbances, which most often become noticeable between the ages of 35 and 50 [1]. Assessment of Huntington disease age of onset (AO), that is, the point in time when a carrier of the expanded allele develops unequivocal HD signs [3], remains to be clearly defined at the phenotypic level, as different criteria are being used to estimate AO. Involuntary movements, such as chorea, are the most distinctive HD symptom that can be established with reliability, and their debut commonly defines HD age of onset [4]. Some authors have defined AO as the age at which the first possible symptom is detected [6,7,8]
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