Letter abstract
Nature Genetics 39, 1120 - 1126 (2007)
Published online: 19 August 2007 | doi:10.1038/ng2113
Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1–like phenotype
Hilde Brems1,9, Magdalena Chmara1,2,9, Mourad Sahbatou3,9, Ellen Denayer1, Koji Taniguchi4, Reiko Kato4, Riet Somers1,5, Ludwine Messiaen6, Sofie De Schepper7, Jean-Pierre Fryns1, Jan Cools1,5, Peter Marynen1,5, Gilles Thomas3,8, Akihiko Yoshimura4 & Eric Legius1
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.
- Department of Human Genetics, Catholic University Leuven, 3000 Leuven, Belgium.
- Department of Biology and Genetics, Medical University of Gdansk, Gdansk, Poland.
- Fondation Jean Dausset–CEPH, 75010 Paris, France.
- Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
- Human Genome Laboratory, Department of Molecular and Developmental Genetics, Flanders Institute for Biotechnology (VIB), Leuven, Belgium.
- Medical Genomics Laboratory, Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
- Department of Dermatology, Ghent University Hospital, Ghent, Belgium.
- Department of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
- These authors contributed equally to this work.
Correspondence to: Eric Legius1 e-mail: Eric.Legius@uz.kuleuven.be
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