Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis

Nature Genetics volume 20, pages 358–361 (1998)Cite this article

Abstract

Partial absence of the sacrum is a rare congenital defect which also occurs as an autosomal dominant trait; association with anterior meningocoele, presacral teratoma and anorectal abnormalities constitutes the Currarino triad1 (MIM 176450). Malformation at the caudal end of the developing notochord at approximately Carnegie stage 7 (16 post-ovulatory days), which results in aberrant secondary neurulation, can explain the observed pattern of anomalies2,3,4. We previously reported linkage to 7q36 markers in two dominantly inherited sacral agenesis families2. We now present data refining the initial subchromosomal localization in several additional hereditary sacral agenesis (HSA) families. We excluded several candidate genes before identifying patient-specific mutations in a homeobox gene, HLXB9, which was previously reported to map to 1q41-q42.1 and to be expressed in lymphoid and pancreatic tissues5,6.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Physical map of the 7q36 region encompassing the HSA gene.
Figure 2: Haplotype analyses.
Figure 3: HLXB9 expression in the sacral region.
Figure 4: HLXB9 organization and mutation identification.

Similar content being viewed by others

References

  1. Currarino, G., Coln, D. & Votteler, T. Triad of anorectal, sacral, and presacral anomalies. Am. J. Roentgenol. 137, 395– 398 (1981).

    Article  CAS  Google Scholar 

  2. Lynch, S.A. et al. A gene for autosomal dominant sacral agenesis maps to the holoprosencephanly region at 7q36. Nature Genet. 11 , 93–95 (1995).

    Article  CAS  Google Scholar 

  3. Copp, A.J. & Brook, F.A. Does lumbosacral spina bifida arise by failure of neural folding or by defective canalisation? J. Med. Genet. 26, 160–166 ( 1989).

    Article  CAS  Google Scholar 

  4. Placzek, M. The role of the notochord and floor plate in inductive interactions. Curr. Opin. Genet. Dev. 5, 499–506 (1995).

    Article  CAS  Google Scholar 

  5. Najfeld, V. et al. Two diverged human homeobox genes involved in the differentiation of human hematopoietic progenitors map to chromosome-1, bands-q41-42.1. Genes Chromosomes Cancer 5, 343–347 (1992).

    Article  CAS  Google Scholar 

  6. Harrison, K.A., Druey, K.M., Deguchi, Y., Tuscano, J.M. & Kehrl, J.H. A novel human homeobox gene distantly related to proboscipedia is expressed in lymphoid and pancreatic tissues. J. Biol. Chem. 269, 19968–19975 ( 1994).

    CAS  PubMed  Google Scholar 

  7. Joyner, A.L. & Martin, G.R. En-1 and En-2, two mouse genes with sequence homology to the Drosophila engrailed gene: expression during embryogenesis. Genes Dev. 1, 29–38 (1987).

    Article  CAS  Google Scholar 

  8. Belloni, E. et al. Identification of Sonic hedgehog as a candidate gene responsible for holoprosencephaly. Nature Genet. 14, 353–356 (1996).

    Article  CAS  Google Scholar 

  9. Roessler, E. et al. Mutations in the human Sonic hedgehog gene cause holoprosencephaly. Nature Genet. 14, 357– 360 (1996).

    Article  CAS  Google Scholar 

  10. Roessler, E. et al. Mutations in the carboxy-terminal domain of Sonic hedgehog cause holoprosencephaly. Hum. Mol. Genet. 6, 1847–1853 (1997).

    Article  CAS  Google Scholar 

  11. Chiang, C. et al. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383, 407– 413 (1996).

    Article  CAS  Google Scholar 

  12. Vargas, F.R. et al. Analysis of the human Sonic hedgehog coding and promoter regions in sacral agenesis, triphalangeal thumb, and mirror polydactyly. Hum. Genet. 102, 387–392 (1998).

    Article  CAS  Google Scholar 

  13. Saha, M.S., Miles, R.R. & Grainger, R.M. Dorsal-ventral patterning during neural induction in Xenopus: Assessment of spinal cord regionalization with xHLXB9 , a marker for the motor neuron region. Dev. Biol. 187, 209–223 (1997).

    Article  CAS  Google Scholar 

  14. Masuno, M. et al. Currarino triad with a terminal deletion 7q35–qter. J. Med. Genet. 33, 877– 878 (1996).

    Article  CAS  Google Scholar 

  15. Morichon-Delvallez, N., Delezoide, A.L. & Vekemans, M. Holoprosencephaly and sacral agensis in a fetus with a terminal deletion 7q36-7qter. J. Med. Gent. 30, 521–524 (1997).

    Article  Google Scholar 

  16. Savage, N.M., Maclachlan, N.A., Joyce, C.A., Moore, I.E. & Crolla, J.A. Isolated sacral agenesis in a fetus monosomic for 7q36.1-qter. J. Med. Genet. 34, 866–868 (1997).

    Article  CAS  Google Scholar 

  17. Anonymous. Short polyalanine expansion: a new class of triplet repeat disorder. Clin. Genet. 53, 333–334 (1998).

  18. Pang, D. Sacral agenesis and caudal spinal malformations. Neurosurg. 32, 755–778 (1993).

    Article  CAS  Google Scholar 

  19. Harlow, C.L., Partington, M.D. & Thieme, G.A. Lumbosacral agenesis: clinical characteristics, imaging and embryogenesis. Pediatr. Neurosurg. 23, 140–147 (1995).

    Article  CAS  Google Scholar 

  20. Kalter, H. Case reports of malformations associated with maternal diabetes: history and critique. Clin. Genet. 43, 174– 179 (1993).

    Article  CAS  Google Scholar 

  21. Lanoue, L. et al. Limb, genital, CNS, and facial malformations result from gene/environment-induced cholesterol deficiency: further evidence for a link to sonic hedgehog. Am. J. Med. Genet. 73, 24–31 (1997).

    Article  CAS  Google Scholar 

  22. O'Riordain, D.S., O'Connell, P.R. & Kirwan, W.O. Hereditary sacral agenesis with presacral mass and anorectal stenosis: the Currarino Triad. Br. J. Surg. 78, 536–538 (1991).

    Article  CAS  Google Scholar 

  23. Hardwicke, R.J., Onikul, E., De Silva, M., Glasson, M.J. & Gaskin, K.J. Partial sacral agenesis with constipation: a report of one family. J. Paediatr. Child Health 28, 328–330 (1992).

    Article  Google Scholar 

  24. Vargas, E.C. et al. Anomalies du sacrum et deficit de fermeture du tube neural manifestations differentes d'une meme maladie genetique? Pediatrie 47, 273–277 ( 1992).

    Google Scholar 

  25. Tsukurov, O. et al. A complex bilateral polysyndactyly disease locus maps to 7q36. Nature Genet. 6, 282– 286 (1994).

    Article  CAS  Google Scholar 

  26. Bullen, P., Robson, S.C. & Strachan, T. Establishing new human embryo collections for documenting gene expression in early human development. in Molecular Genetics of Early Human Development (BIOS Scientific Publishers, Oxford, 1997).

    Google Scholar 

  27. Lako, M., et al. A novel mammalian Wnt gene, WNT8B, shows brain-restricted expression in early development, with sharply delimited expression boundaries in the developing brain. Hum. Molec. Genet. 7, 813–822 (1998).

    Article  CAS  Google Scholar 

  28. Mackay, M. et al. Chromosomal localization in mouse and human of the vasoactive intestinal peptide receptor type 2 gene: a possible contributor to the holoprosencephaly 3 phenotype. Genomics 37, 345– 353 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We are grateful to patients and their relatives who have assisted this study by providing samples for our analyses and to several additional clinicians and health service staff who assisted in sample collection. We gratefully acknowledge a gift of an HLXB9 cDNA clone from J. Kehrl. We are grateful for financial support for this work from the UK Medical Research Council, the EC and the Sir Jules Thorn Charitable Trust. We would also like to acknowledge our debt to the UK HGMP Resource centre for providing many clone and informatics resources. Thanks to A. Copp, R. Winter and J. Kehrl for helpful discussions, and to P. Bond and P. Nixon for their previous contributions to this project.

Author information

Author notes

  1. Alison J. Ross, Victor Ruiz-Perez and Yiming Wang: These authors contributed equally to this work

Authors and Affiliations

  1. Human Genetics Unit, School of Biochemistry and Genetics, University of Newcastle upon Tyne, Ridley Building, Claremont Place, Newcastle upon Tyne, NE1 7RU, UK

    Alison J. Ross, Victor Ruiz-Perez, Yiming Wang, Donna-Marie Hagan, Sally A. Lynch, Susan Lindsay, David I. Wilson, John Burn & Tom Strachan.

  2. Department of Genetics, Hospital for Sick Children, Toronto, Canada

    Steve Scherer & Elena Belloni

  3. Molecular Medicine Unit, Institute of Child Health, University of London, 30 Guilford Street, London, WC1N 1EH, UK

    Emily Custard, Roy Wadey, Frances Goodman & Pete Scambler

  4. Department of Medical Genetics, Ulleval University Hospital, Box 1036, Blindern, Oslo, 0315, Norway

    Karen Helene Orstavik

  5. Department of Pediatric Surgery, The National Hospital, Oslo, 0027, Norway

    Tom Monclair

  6. Department of Obstetrics and Gynaecology, University of Newcastle upon Tyne, Victoria Road, Newcastle upon Tyne, UK

    Steve Robson

  7. Clinical Genetics Unit, Institute of Child Health, University of London, 30 Guilford Street, London, WC1N 1EH, UK

    William Reardon

Authors
  1. Alison J. Ross
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Victor Ruiz-Perez
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yiming Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Donna-Marie Hagan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Steve Scherer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sally A. Lynch
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Susan Lindsay
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Emily Custard
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Elena Belloni
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. David I. Wilson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Roy Wadey
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Frances Goodman
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Karen Helene Orstavik
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Tom Monclair
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Steve Robson
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. William Reardon
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. John Burn
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Pete Scambler
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Tom Strachan.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Tom Strachan..

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ross, A., Ruiz-Perez, V., Wang, Y. et al. A homeobox gene, HLXB9, is the major locus for dominantly inherited sacral agenesis. Nat Genet 20, 358–361 (1998). https://doi.org/10.1038/3828

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/3828

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing