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| Item Type: | Article |
|---|---|
| Title: | Single molecule real time sequencing in ADTKD-MUC1 allows complete assembly of the VNTR and exact positioning of causative mutations |
| Creators Name: | Wenzel, A. and Altmueller, J. and Ekici, A.B. and Popp, B. and Stueber, K. and Thiele, H. and Pannes, A. and Staubach, S. and Salido, E. and Nuernberg, P. and Reinhardt, R. and Reis, A. and Rump, P. and Hanisch, F.G. and Wolf, M.T.F. and Wiesener, M. and Huettel, B. and Beck, B.B. |
| Abstract: | Recently, the Mucin-1 (MUC1) gene has been identified as a causal gene of autosomal dominant tubulointerstitial kidney disease (ADTKD). Most causative mutations are buried within a GC-rich 60 basepair variable number of tandem repeat (VNTR), which escapes identification by massive parallel sequencing methods due to the complexity of the VNTR. We established long read single molecule real time sequencing (SMRT) targeted to the MUC1-VNTR as an alternative strategy to the snapshot assay. Our approach allows complete VNTR assembly, thereby enabling the detection of all variants residing within the VNTR and simultaneous determination of VNTR length. We present high resolution data on the VNTR architecture for a cohort of snapshot positive (n = 9) and negative (n = 7) ADTKD families. By SMRT sequencing we could confirm the diagnosis in all previously tested cases, reconstruct both VNTR alleles and determine the exact position of the causative variant in eight of nine families. This study demonstrates that precise positioning of the causative mutation(s) and identification of other coding and noncoding sequence variants in ADTKD-MUC1 is feasible. SMRT sequencing could provide a powerful tool to uncover potential factors encoded within the VNTR that associate with intra- and interfamilial phenotype variability of MUC1 related kidney disease. |
| Keywords: | Disease Genetics, Molecular Medicine |
| Source: | Scientific Reports |
| ISSN: | 2045-2322 |
| Publisher: | Nature Publishing Group |
| Volume: | 8 |
| Number: | 1 |
| Page Range: | 4170 |
| Date: | 8 March 2018 |
| Official Publication: | https://doi.org/10.1038/s41598-018-22428-0 |
| PubMed: | View item in PubMed |
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