DRPLA transgenic mouse substrains carrying single copy of full-length mutant human DRPLA gene with variable sizes of expanded CAG repeats exhibit CAG repeat length- and age-dependent changes in behavioral abnormalities and gene expression profiles

Suzuki, Kazushi; Zhou, Jiayi; Sato, Toshiya; Takao, Keizo; Miyagawa, T.; Oyake, Mutsuo; Yamada, Mako; Takahashi, Hitoshi; Takahashi, Yūji; Goto, Jun; Tsuji, Shoji

doi:10.1016/j.nbd.2012.01.014

Cited by 24 publications

(26 citation statements)

References 53 publications

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“…Simple behavioral traits have been used in ENU mutagenesis projects 7 to identify fully penetrant mutations, and standard behavioral tests have been used to study genetic polymorphisms in a series of expanded repeats 8 . More recently, machine learning techniques have been used to advance the investigation of phenotype-genotype relationships in autism spectrum disorder 9 .…”

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confidence: 99%

Large-scale phenome analysis defines a behavioral signature for Huntington's disease genotype in mice

et al. 2016

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Rapid technological advances for the frequent monitoring of health parameters have raised the intriguing possibility that an individual's genotype could be predicted from phenotypic data alone. Here we used a machine learning approach to analyze the phenotypic effects of polymorphic mutations in a mouse model of Huntington's disease that determine disease presentation and age of onset. The resulting model correlated variation across 3,086 behavioral traits with seven different CAG-repeat lengths in the huntingtin gene (Htt). We selected behavioral signatures for age and CAG-repeat length that most robustly distinguished between mouse lines and validated the model by correctly predicting the repeat length of a blinded mouse line. Sufficient discriminatory power to accurately predict genotype required combined analysis of >200 phenotypic features. Our results suggest that autosomal dominant disease-causing mutations could be predicted through the use of subtle behavioral signatures that emerge in large-scale, combinatorial analyses. Our work provides an open data platform that we now share with the research community to aid efforts focused on understanding the pathways that link behavioral consequences to genetic variation in Huntington's disease.

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confidence: 99%

Large-scale phenome analysis defines a behavioral signature for Huntington's disease genotype in mice

et al. 2016

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“…Repeat rates of the CAG number in these two individuals are 18 and 19, and Huntington's disease can be ruled out. A diagnosis of Huntington's disease-like-2 could be made from detection of additional genes, including DRPLA , JPH3 , and TBP , whose mutation results in the neural system movement disorders, dentatorubral-pallidoluysian atrophy, Huntington's disease-like-2, and spinocerebellar ataxia type 17, respectively[52535455565758]. No IT15 mutations are found in 1% of patients suffering from clinical features of Huntington's disease[365960].…”

Section: Discussionmentioning

confidence: 99%

Examination of Huntington′s disease in a Chinese family

et al. 2014

Neural Regen Res

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We report brain imaging and genetic diagnosis in a family from Wuhan, China, with a history of Huntington's disease. Among 17 family members across three generations, four patients (II2, II6, III5, and III9) show typical Huntington's disease, involuntary dance-like movements. Magnetic resonance imaging found lateral ventricular atrophy in three members (II2, II6, and III5). Moreover, genetic analysis identified abnormally amplified CAG sequence repeats (> 40) in two members (III5 and III9). Among borderline cases, with clinical symptoms and brain imaging features of Huntington's disease, two cases were identified (II2 and II6), but shown by mutation analysis for CAG expansions in the important transcript 15 gene, to be non-Huntington's disease. Our findings suggest that clinical diagnosis of Huntington's disease requires a combination of clinical symptoms, radiological changes, and genetic diagnosis.

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“…A valid model was serendipitously generated by massive expansion of CAG repeats identified in offspring mosaic mice and by subsequent breeding to a pure strain with a 129 polyQ tract (Sakai et al, 2006;Sato et al, 2009). Further related substrains with 113 and 96 CAG repeats were generated from the Q129 strain (Suzuki et al, 2012).…”

Section: Drpla Mouse Modelsmentioning

confidence: 99%