Molecular characterization of ENU mouse mutagenesis and archives

Sakuraba, Yoshiyuki; Sezutsu, Hideki; Takahasi, K. Ryo; Tsuchihashi, Keiko; Ichikawa, Rie; Fujimoto, Naomi; Kaneko, Satoko; Nakai, Yuji; Uchiyama, Masaaki; Goda, Noriko; Motoi, Rika; Ikeda, Ami; Karashima, Yuko; Inoue, Masayasu; Kaneda, Hideki; Masuya, Hiroshi; Minowa, Osamu; Noguchi, Hideki; Toyoda, Atsushi; Sakaki, Yoshiyuki; Wakana, Shigeharu; Noda, Tetsuo; Shiroishi, Toshihiko; Gondo, Yoichi

doi:10.1016/j.bbrc.2005.08.134

Cited by 80 publications

(94 citation statements)

References 28 publications

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“…49 In a collaboration with the RIKEN Genomic Sciences Centre (Yokohama, Japan), Clapcote et al 50 screened the large exon 2 of Disc1 and identified two different missense mutations, a Q (glutamine) to L (leucine) change at aminoacid position 31 (Q31L) or a L (leucine) to P (proline) change at position 100 (L100P). The brain anatomical, behavioural, pharmacological and biochemical phenotypes of these two Disc1 missense mutants were also investigated 50 (Figure 1b).…”

Section: The Phenotype Of Mouse Disc1 Variantsmentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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The DISC locus is located at the breakpoint of a balanced t(1;11) chromosomal translocation in a large and unique Scottish family. This translocation segregates in a highly statistically significant manner with a broad diagnosis of psychiatric illness, including schizophrenia, bipolar disorder and major depression, as well as with a narrow diagnosis of schizophrenia alone. Two novel genes were identified at this locus and due to the high prevalence of schizophrenia in this family, they were named Disrupted-in-Schizophrenia-1 (DISC1) and Disrupted-in-Schizophrenia-2 (DISC2). DISC1 encodes a novel multifunctional scaffold protein, whereas DISC2 is a putative noncoding RNA gene antisense to DISC1. A number of independent genetic linkage and association studies in diverse populations support the original linkage findings in the Scottish family and genetic evidence now implicates the DISC locus in susceptibility to schizophrenia, schizoaffective disorder, bipolar disorder and major depression as well as various cognitive traits. Despite this, with the exception of the t(1;11) translocation, robust evidence for a functional variant(s) is still lacking and genetic heterogeneity is likely. Of the two genes identified at this locus, DISC1 has been prioritized as the most probable candidate susceptibility gene for psychiatric illness, as its protein sequence is directly disrupted by the translocation. Much research has been undertaken in recent years to elucidate the biological functions of the DISC1 protein and to further our understanding of how it contributes to the pathogenesis of schizophrenia. These data are the main subject of this review; however, the potential involvement of DISC2 in the pathogenesis of psychiatric illness is also discussed. A detailed picture of DISC1 function is now emerging, which encompasses roles in neurodevelopment, cytoskeletal function and cAMP signalling, and several DISC1 interactors have also been defined as independent genetic susceptibility factors for psychiatric illness. DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention. Molecular Psychiatry (2008) 13, 36-64; doi:10.1038/sj.mp.4002106; published online 2 October 2007 Keywords: schizophrenia; bipolar disorder; depression; DISC1; DISC2; mouse models Genetics of DISC1 discoverySt Clair et al. 1 first reported a Scottish family with a high loading of major mental illness, which cosegregates with a t(1;11) translocation. Long-term follow-up of this family over a period of 30 years has reported 87 family members, of whom 37 carry the translocation. 2 Of 29 individuals carrying the translocation, for whom psychiatric assessment was possible, 7 have a diagnosis of schizophrenia, 1 has a diagnosis of bipolar disorder and 10 cases of recurrent major depression were also reported. 2 Thus, 18 of 29 translocation carriers are diagnosed with major mental illness whereas none of...

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Section: The Phenotype Of Mouse Disc1 Variantsmentioning

confidence: 99%

The DISC locus in psychiatric illness

et al. 2007

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“…The random distribution of ENU-induced mutations has been experimentally confirmed [30]. It implies that if we screen 461 bp of the target sequence after PCR amplification of 10,000 G1 mouse genomic DNA samples, we may find 4.61 ENU-induced mutations on average and may find at least one ENU-induced mutation with 99% probability.…”

Section: High Throughput Mutation Discovery Systemsmentioning

confidence: 79%

“…Many other phenotype-driven ENU mutagenesis projects followed in 2000, for instance, Baylor College of Medicine, Jackson Laboratory, TMGC in US and CMHD in Canada. Using the ENU mutagenesis, RIKEN [12,30], MRC [26], and Oak Ridge National Laboratory [20] also started gene-driven mutagenesis in 2000.…”

Section: -Review-mentioning

confidence: 99%

“…We conducted a feasibility study of screening of ENU-induced mutations in G1 genomic DNAs and the ENU-induced mutation rate was primarily estimated to be 1 mutation per megabase pairs (Mb) in G1 genomic DNA [13,30,31]. In other words, 3,000 ENUinduced mutations may be randomly induced in a given G1 mouse, since the size of the mouse genome is approximately 3 × 10 9 bp.…”

Section: Mutant Mouse Librarymentioning

confidence: 99%

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ENU-Based Gene-Driven Mutagenesis in the Mouse: A Next-Generation Gene-Targeting System

et al. 2010

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Abstract:As a new mouse mutant resource, the RIKEN ENU-based gene-driven mutagenesis system in the mouse has been available to the research community since 2002. By using random base-substitution mutagenesis with ENU, a new reverse genetics infrastructure has been developed as a next-generation gene-targeting system. The construction of a largescale mutant mouse library and high-throughput mutation discovery systems were the keys making it practically feasible. The RIKEN mutant mouse library consists of ~10,000 G1 mice, within which 100-150 mutant strains have been established based on users' requests every year. Use of the system is very simple: users 1) download an application form from our web site and send to us, and 2) design the PCR primers for the target gene. Then, we screen the RIKEN mutant mouse library and report all the detected mutations to the user. From among the allelic series of discovered mutations, users decide which mutant strain(s) to analyze and request the live mutant strain for functional studies of the target gene. Users have been reporting various functional mutations in the RIKEN mutant mouse library: e.g., missense, knockout-type and even functional non-coding mutations. In the near future, next-generation re-sequencing systems should drastically enhance the utility of the ENUbased gene-driven mutagenesis not only for the mouse but also for other species.

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“…The most effective dose of ENU (that induces the most mutations with the least lethality) creates one mutation every 0.1-1 MB, based on direct sequencing data (Beier, 2000;Concepcion et al, 2004;Sakuraba et al, 2005), or roughly 3,000 nucleotide changes per genome. The vast majority of these mutations lie in non-coding DNA and do not affect gene function.…”

Section: Mutants and More Mutantsmentioning

confidence: 99%

Uncovering the uncharacterized and unexpected: Unbiased phenotype‐driven screens in the mouse

Caspary

Anderson

2006

Developmental Dynamics

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Phenotype-based chemical mutagenesis screens for mouse mutations have undergone a transformation in the past five years from a potential approach to a practical tool. This change has been driven by the relative ease of identifying causative mutations now that the complete genome sequence is available. These unbiased screens make it possible to identify genes, gene functions and processes that are uniquely important to mammals. In addition, because chemical mutagenesis generally induces point mutations, these alleles often uncover previously unappreciated functions of known proteins. Here we provide examples of the success stories from forward genetic screens, emphasizing the examples that illustrate the discovery of mammalian-specific processes that could not be discovered in other model organisms. As the efficiency of sequencing and mutation detection continues to improve, it is likely that forward genetic screens will provide an even more important part of the repertoire of mouse genetics in the future. Developmental Dynamics 235:2412-2423, 2006.

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Molecular characterization of ENU mouse mutagenesis and archives

Cited by 80 publications

References 28 publications

The DISC locus in psychiatric illness

The DISC locus in psychiatric illness

ENU-Based Gene-Driven Mutagenesis in the Mouse: A Next-Generation Gene-Targeting System

Uncovering the uncharacterized and unexpected: Unbiased phenotype‐driven screens in the mouse

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