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⇱ Mutations in PHF6 are associated with Börjeson–Forssman –Lehmann syndrome | Nature Genetics

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Abstract

Börjeson–Forssman–Lehmann syndrome (BFLS; OMIM 301900) is characterized by moderate to severe mental retardation, epilepsy, hypogonadism, hypometabolism, obesity with marked gynecomastia, swelling of subcutaneous tissue of the face, narrow palpebral fissure and large but not deformed ears1. Previously, the gene associated with BFLS was localized to 17 Mb in Xq26–q27 (refs 2–4). We have reduced this interval to roughly 9 Mb containing more than 62 genes. Among these, a novel, widely expressed zinc-finger (plant homeodomain (PHD)-like finger) gene (PHF6) had eight different missense and truncation mutations in seven familial and two sporadic cases of BFLS. Transient transfection studies with PHF6 tagged with green fluorescent protein (GFP) showed diffuse nuclear staining with prominent nucleolar accumulation. Such localization, and the presence of two PHD-like zinc fingers, is suggestive of a role for PHF6 in transcription.

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Figure 1: Physical map of the BFLS critical region and genomic organization of PHF6.
Figure 2: Mutations in individuals with BFLS.
Figure 3: Annotated protein sequence of PHF6 and its partially sequenced orthologs.
Figure 4: Section in situ hybridization on mouse embryos.
Figure 5: Subcellular localization of recombinant PHF6 and analysis of putative NLS localization signals.

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Acknowledgements

We thank the members of the families studied for their participation; C. Schwartz and J.P. Fryns for contributing samples; M. Lagerström Fermer for providing samples from the family affected with Gustavson syndrome; S. McDonnell and C. Derwas for help with cell culture; and M. Partington and G. Sutherland for critical reading of the manuscript. K.M.L. was supported by the Adelaide Research Scholarship from Adelaide University. This work was supported by the National Health and Medical Research Council of Australia.

Author information

Authors and Affiliations

  1. Department of Cytogenetics and Molecular Genetics, Centre for Medical Genetics, Women's and Children's Hospital, 72 King William Rd., North Adelaide, 5006, SA, Australia

    Karen M. Lower, Marie A. Shaw, Ági K. Gedeon, John C. Mulley & Jozef Gécz

  2. Department of Paediatrics, University of Adelaide, Adelaide, 5001, SA, Australia

    Karen M. Lower & Jozef Gécz

  3. Hunter Genetics and University of Newcastle, New South Wales, Waratah, Australia

    Gillian Turner

  4. Regional Genetic Service, St. Mary's Hospital, Manchester, UK

    Bronwyn A. Kerr & Jill Clayton-Smith

  5. Department of Pediatrics and Neurology, University of Iowa Hospital and Clinics, Iowa City, Iowa, USA

    Katherine D. Mathews

  6. Division of Medical Genetics, Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA

    Susan Schelley & H. Eugene Hoyme

  7. Genetic Health Services Victoria, Royal Children's Hospital, Melbourne, Victoria, Australia

    Susan M. White & Martin B. Delatycki

  8. Department of Clinical Genetics, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne, UK

    Anne K. Lampe

  9. Department of Medical Genetics, Churchill Hospital, Old Road, Oxford, Headington, UK

    Helen Stewart

  10. Department of Human Genetics, University Medical Centre, Nijmegen, The Netherlands

    Conny M. A. van Ravenswaay & Bert B. A. de Vries

  11. Department of Molecular and Medical Genetics, Oregon Health Sciences University, Portland, Oregon, USA

    Barbara Cox & Markus Grompe

  12. Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia

    Shelley Ross & Paul Thomas

  13. Department of Molecular Biosciences, University of Adelaide, Adelaide, Australia

    John C. Mulley

Authors
  1. Karen M. Lower
  2. Gillian Turner
  3. Bronwyn A. Kerr
  4. Katherine D. Mathews
  5. Marie A. Shaw
  6. Ági K. Gedeon
  7. Susan Schelley
  8. H. Eugene Hoyme
  9. Susan M. White
  10. Martin B. Delatycki
  11. Anne K. Lampe
  12. Jill Clayton-Smith
  13. Helen Stewart
  14. Conny M. A. van Ravenswaay
  15. Bert B. A. de Vries
  16. Barbara Cox
  17. Markus Grompe
  18. Shelley Ross
  19. Paul Thomas
  20. John C. Mulley
  21. Jozef Gécz

Corresponding author

Correspondence to Jozef Gécz.

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Competing interests

The authors declare no competing financial interests.

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Lower, K., Turner, G., Kerr, B. et al. Mutations in PHF6 are associated with Börjeson–Forssman –Lehmann syndrome. Nat Genet 32, 661–665 (2002). https://doi.org/10.1038/ng1040

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  • DOI: https://doi.org/10.1038/ng1040

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