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Retrotransposition disrupting EBP in a girl and her mother with X-linked dominant chondrodysplasia punctata

Journal of Human Genetics volume 67, pages 303–306 (2022)Cite this article

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Abstract

X-linked dominant chondrodysplasia punctata (CDPX2) is a rare congenital disorder caused by pathogenic variants in EBP on Xp11.23. We encountered a girl and her mother with CDPX2-compatible phenotypes including punctiform calcification in the neonatal period of the girl, and asymmetric limb shortening and ichthyosis following the Blaschko lines in both subjects. Although Sanger direct sequencing failed to reveal a disease-causing variant in EBP, whole genome sequencing (WGS) followed by Manta analysis identified a ~ 4.5 kb insertion at EBP exon 2 of both subjects. The insertion was associated with the hallmarks of retrotransposition such as an antisense poly(A) tail, a target site duplication, and a consensus endonuclease cleavage site, and the inserted sequence harbored full-length SVA_F1 element with 5′- and 3′-transductions containing the Alu sequence. The results imply the relevance of retrotransposition to the human genetic diseases and the usefulness of WGS in the identification of retrotransposition.

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References

  1. Happle R. X-linked dominant chondrodysplasia punctata. Review of literature and report of a case. Hum Genet. 1979;53:65–73.

    Article  CAS  Google Scholar 

  2. Braverman N, Lin P, Moebius FF, Obie C, Moser A, Glossmann H, et al. Mutations in the gene encoding 3 beta-hydroxysteroid-delta 8, delta 7-isomerase cause X-linked dominant Conradi-Hünermann syndrome. Nat Genet. 1999;22:291–4.

    Article  CAS  Google Scholar 

  3. Batzer MA, Deininger PL. Alu repeats and human genomic diversity. Nat Rev Genet. 2002;3:370–9.

    Article  CAS  Google Scholar 

  4. Hancks DC, Kazazian HH Jr. Roles for retrotransposon insertions in human disease. Mob DNA 2016;7:9.

    Article  Google Scholar 

  5. Hohjoh H, Singer MF. Sequence-specific single-strand RNA binding protein encoded by the human LINE-1 retrotransposon. EMBO J. 1997;16:6034–43.

    Article  CAS  Google Scholar 

  6. Martin SL, Bushman FD. Nucleic acid chaperone activity of the ORF1 protein from the mouse LINE-1 retrotransposon. Mol Cell Biol. 2001;21:467–75.

    Article  CAS  Google Scholar 

  7. Mathias SL, Scott AF, Kazazian HH Jr, Boeke JD, Gabriel A. Reverse transcriptase encoded by a human transposable element. Science 1991;254:1808–10.

    Article  CAS  Google Scholar 

  8. Feng Q, Moran JV, Kazazian HH Jr, Boeke JD. Human L1 retrotransposon encodes a conserved endonuclease required for retrotransposition. Cell 1996;87:905–16.

    Article  CAS  Google Scholar 

  9. Dewannieux M, Esnault C, Heidmann T. LINE-mediated retrotransposition of marked Alu sequences. Nat Genet. 2003;35:41–48.

    Article  CAS  Google Scholar 

  10. Ostertag EM, Goodier JL, Zhang Y, Kazazian HH Jr. SVA elements are nonautonomous retrotransposons that cause disease in humans. Am J Hum Genet. 2003;73:1444–51.

    Article  CAS  Google Scholar 

  11. Esnault C, Maestre J, Heidmann T. Human LINE retrotransposons generate processed pseudogenes. Nat Genet. 2000;24:363–7.

    Article  CAS  Google Scholar 

  12. Wei W, Gilbert N, Ooi SL, Lawler JF, Ostertag EM, Kazazian HH, et al. Human L1 retrotransposition: cis preference versus trans complementation. Mol Cell Biol. 2001;21:1429–39.

    Article  CAS  Google Scholar 

  13. Wang H, Xing J, Grover D, Hedges DJ, Han K, Walker JA, et al. SVA elements: a hominid-specific retroposon family. J Mol Biol. 2005;354:994–1007.

    Article  CAS  Google Scholar 

  14. Damert A, Raiz J, Horn AV, Löwer J, Wang H, Xing J, et al. 5’-Transducing SVA retrotransposon groups spread efficiently throughout the human genome. Genome Res. 2009;19:1992–2008.

    Article  CAS  Google Scholar 

  15. Honda A, Yamashita K, Miyazaki H, Shirai M, Ikegami T, Xu G, et al. Highly sensitive analysis of sterol profiles in human serum by LC-ESI-MS/MS. J Lipid Res. 2008;49:2063–73.

    Article  CAS  Google Scholar 

  16. Honda A, Miyazaki T, Ikegami T, Iwamoto J, Yamashita K, Numazawa M, et al. Highly sensitive and specific analysis of sterol profiles in biological samples by HPLC-ESI-MS/MS. J Steroid Biochem Mol Biol. 2010;121:556–64.

    Article  CAS  Google Scholar 

  17. Hiraide T, Nakashima M, Ikeda T, Tanaka D, Osaka H, Saitsu H. Identification of a deep intronic POLR3A variant causing inclusion of a pseudoexon derived from an Alu element in Pol III-related leukodystrophy. J Hum Genet. 2020;65:921–5.

    Article  CAS  Google Scholar 

  18. Chen X, Schulz-Trieglaff O, Shaw R, Barnes B, Schlesinger F, Källberg M, et al. Manta: rapid detection of structural variants and indels for germline and cancer sequencing applications. Bioinformatics 2016;32:1220–2.

    Article  CAS  Google Scholar 

  19. Bantysh OB, Buzdin AA. Novel family of human transposable elements formed due to fusion of the first exon of gene MAST2 with retrotransposon SVA. Biochem (Mosc). 2009;74:1393–9.

    Article  CAS  Google Scholar 

  20. Hancks DC, Ewing AD, Chen JE, Tokunaga K, Kazazian HH Jr. Exon-trapping mediated by the human retrotransposon SVA. Genome Res. 2009;19:1983–91.

    Article  CAS  Google Scholar 

  21. Miyamoto S, Nakashima M, Ohashi T, Hiraide T, Kurosawa K, Yamamoto T, et al. A case of de novo splice site variant in SLC35A2 showing developmental delays, spastic paraplegia, and delayed myelination. Mol Genet Genom Med. 2019;7:e814.

    Google Scholar 

  22. Neerman N, Faust G, Meeks N, Modai S, Kalfon L, Falik-Zaccai T, et al. A clinically validated whole genome pipeline for structural variant detection and analysis. BMC Genomics. 2019;20:545.

    Article  Google Scholar 

  23. Symer DE, Connelly C, Szak ST, Caputo EM, Cost GJ, Parmigiani G, et al. Human l1 retrotransposition is associated with genetic instability in vivo. Cell 2002;110:327–38.

    Article  CAS  Google Scholar 

  24. Moran JV, DeBerardinis RJ, Kazazian HH Jr. Exon shuffling by L1 retrotransposition. Science 1999;283:1530–4.

    Article  CAS  Google Scholar 

  25. Szak ST, Pickeral OK, Landsman D, Boeke JD. Identifying related L1 retrotransposons by analyzing 3’ transduced sequences. Genome Biol. 2003;4:R30.

    Article  Google Scholar 

  26. Cost GJ, Feng Q, Jacquier A, Boeke JD. Human L1 element target-primed reverse transcription in vitro. EMBO J. 2002;21:5899–910.

    Article  CAS  Google Scholar 

  27. Steijlen PM, van Geel M, Vreeburg M, Marcus-Soekarman D, Spaapen LJ, Castelijns FC, et al. Novel EBP gene mutations in Conradi-Hünermann-Happle syndrome. Br J Dermatol. 2007;157:1225–9.

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank the patients for participating in this work. We also thank Ms. Aya Kitamoto, and Mr. Naoki Adachi for their technical support. This work was supported by the grants from Japan Agency for Medical Research and Development (AMED) (JP19ek0109297 to H.S. and JP21ek0109549 to T.O.).

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Authors and Affiliations

  1. Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Takuya Hiraide, Yohei Masunaga & Tsutomu Ogata

  2. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Takuya Hiraide, Mitsuko Nakashima, Hirotomo Saitsu & Tsutomu Ogata

  3. Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan

    Akira Honda

  4. Hamamatsu Child Health and Developmental Medicine, Hamamatsu, Japan

    Fumiko Kato & Tokiko Fukuda

  5. Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan

    Maki Fukami

  6. Department of Pediatrics, Hamamatsu Medical Center, Hamamatsu, Japan

    Tsutomu Ogata

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  1. Takuya Hiraide
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  2. Yohei Masunaga
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  3. Akira Honda
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  4. Fumiko Kato
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  5. Tokiko Fukuda
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  7. Mitsuko Nakashima
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  8. Hirotomo Saitsu
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  9. Tsutomu Ogata
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Correspondence to Tsutomu Ogata.

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Hiraide, T., Masunaga, Y., Honda, A. et al. Retrotransposition disrupting EBP in a girl and her mother with X-linked dominant chondrodysplasia punctata. J Hum Genet 67, 303–306 (2022). https://doi.org/10.1038/s10038-021-01000-1

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