2017 Fiscal Year Research-status Report
Establishment of an integrated database of DNA repair deficiency disorders
| Project/Area Number |
17K17806
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| Research Institution | Nagoya University |
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Principal Investigator |
賈 楠 名古屋大学, 環境医学研究所, 特任助教 (90754060)
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Keywords | DDR-deficient disorders / Cockyane Syndrome / UV-sensitive syndrome |
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| Outline of Annual Research Achievements |
DNA damage response (DDR) system is important for maintenance of genome integrity; defects in DDR system can result in deleterious consequences, including cancer and genetic disorders. For more precise diagnosis and better understanding of the mechanisms underlying DDR-deficient disorders, we worked on collecting DDR deficiency patient samples from all over the world, followed by establishment of cell bank, as well as large scale screening of DNA repair activities, gene diagnosis and identification of founder mutations. Till now over 1000 samples have been collected and stocked in proper way. We, together with collaborators from Italy, France and UK, finished diagnosis of 124 patients with Cockyane Syndrome (CS), and identified 71 novel pathogenic mutations in the CSA and CSB genes. Our results provide insight into previously unreported genotype-phenotype relationships and their relevance for clinical diagnosis.
We also identified several mild cases with R77* mutations in the CSB gene (CS-IV patients). In our research we found distinct cellular responses between CS-IV patients and other severe CS patients after UV damage, and this difference may be related to diverse severity of CS clinical phenotype.
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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
1.We have collected over 1000 samples and have made the cell stock as well as performed gene diagnosis of most of samples.
2.For research on functional analysis of CS and UV-sensitive syndrome (UVSS) patients, we collected samples from with different clinical spectrum including CS-I, CS-II, CS-III and CS-IV, and found the break point to explain diverse CS phenotype.
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| Strategy for Future Research Activity |
1.We will keep on collecting samples, performing gene diagnosis and functional analysis, to identify novel genes and mutations, as well as to search genotype-phenotype correlations underlying DDR deficiency disorders.
2.We are also working on investigate the genotype-phenotype correlations in CS, and going to perform the following experiments: i, identify the common alternative transcripts in all CS-IV patients as they carry the same mutation; ii, investigate whether the putative alternative transcripts are related to the unique cellular response in CS-IV patients after UV damage; iii, generate mouse model for analysis of genotype-phenotype correlation and for drug development.
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| Causes of Carryover |
In this year, most of the collected samples we analyzed are CS patients with mutations in the CSA and CSB genes, which we could perform precise gene diagnosis with standard Sanger Sequence instead of costly Next Generation Sequence (NGS).
The saved budget will be used in: (1) diagnosis of cases with DNA repair defects that unknown genes are involved with NGS and Mass spectrum (MS); (ii) consumables of functional analysis, including RNA-sequence and mice experiments, and et al.
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