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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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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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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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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DOI: https://doi.org/10.1038/ng2113
