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Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1–like phenotype

Nature Genetics volume 39, pages 1120–1126 (2007)Cite this article

Abstract

We report germline loss-of-function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/SPRED family1 of proteins that act as negative regulators of RAS->RAF interaction and mitogen-activated protein kinase (MAPK) signaling2. The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple café-au-lait spots, axillary freckling and macrocephaly. Melanocytes from a café-au-lait spot showed, in addition to the germline SPRED1 mutation, an acquired somatic mutation in the wild-type SPRED1 allele, indicating that complete SPRED1 inactivation is needed to generate a café-au-lait spot in this syndrome. This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS-MAPK pathway3,4. To our knowledge, this is the first report of mutations in the SPRY (SPROUTY)/SPRED family of genes in human disease.

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Figure 1: Pedigrees and clinical photographs.
Figure 2: Exon-intron structure of human SPRED1 showing noncoding sequences as open boxes and protein-coding exons as filled black boxes.
Figure 3: Effect of SPRED1 on the RAS-MAPK pathway.

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Acknowledgements

The authors thank T. de Ravel for critically reading the manuscript, M. De Mil for technical assistance in melanocyte cell culture and F. Okamoto for technical assistance in cell culture and plasmid preparation. H.B. is supported by the Institute for the Promotion of Innovation through Science and Technology in Flanders (IWT-Vlaanderen). M.C. was supported by the Marie Curie European Community fellowship (contract HPMT-CT2001-00273). E.D. is a predoctoral researcher (Aspirant of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen), J.C. is a postdoctoral researcher and E.L. is a part-time clinical researcher of the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen (FWO). This work is also supported by research grants from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (G.0096.02, E.L.) and (G.0507.04, P.M.); by the Interuniversity Attraction Poles (IAP) granted by the Federal Office for Scientific, Technical and Cultural Affairs, Belgium (2002–2006; P5/25) (P.M. and E.L.); by a Concerted Action Grant from the Catholic University Leuven; by the Federation des Maladies Genetiques Orphelines (G.T.) and by grants-in-aid from the Ministry of Education, Science, Technology, Sports, and Culture of Japan (A.Y.). This work was made possible by the Centre of Excellence SymBioSys (Research Council, Catholic University Leuven EF/05/007) (E.L.).

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Author notes

  1. Hilde Brems, Magdalena Chmara and Mourad Sahbatou: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Human Genetics, Catholic University Leuven, Leuven, 3000, Belgium

    Hilde Brems, Magdalena Chmara, Ellen Denayer, Riet Somers, Jean-Pierre Fryns, Jan Cools, Peter Marynen & Eric Legius

  2. Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland

    Magdalena Chmara

  3. Fondation Jean Dausset–CEPH, Paris, 75010, France

    Mourad Sahbatou & Gilles Thomas

  4. Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, 812-8582, Japan

    Koji Taniguchi, Reiko Kato & Akihiko Yoshimura

  5. Department of Molecular and Developmental Genetics, Human Genome Laboratory, Flanders Institute for Biotechnology (VIB), Leuven, Belgium

    Riet Somers, Jan Cools & Peter Marynen

  6. Department of Genetics, Medical Genomics Laboratory, University of Alabama at Birmingham, Birmingham, Alabama, USA.,

    Ludwine Messiaen

  7. Department of Dermatology, Ghent University Hospital, Ghent, Belgium

    Sofie De Schepper

  8. Department of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, 20892, Maryland, USA

    Gilles Thomas

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  1. Hilde Brems
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Contributions

The study was coordinated by H.B., G.T., P.M., A.Y. and E.L.; patient phenotyping was performed by J.-P.F. and E.L. and clinical data collected by E.D.; linkage analysis was done by M.S. and G.T.; NF1 mutation analysis was conducted by L.M. and SPRED1 mutation analysis by H.B., M.C. and E.D.; skin biopsies were carried out by S.D.S. and melanocytes cultured by H.B. and S.D.S.; biochemical analysis was performed by H.B., M.C., E.D., K.T., R.S. and J.C.; mouse characterization was performed by R.K.; the manuscript was written by H.B., M.C., E.D., L.M., S.D.S., A.Y., J.-P.F., J.C., P.M., G.T. and E.L.

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Correspondence to Eric Legius.

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The authors declare no competing financial interests.

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Brems, H., Chmara, M., Sahbatou, M. et al. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1–like phenotype. Nat Genet 39, 1120–1126 (2007). https://doi.org/10.1038/ng2113

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