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

Hilde Brems, Magdalena Chmara, Mourad Sahbatou, Ellen Denayer, Koji Taniguchi, Reiko Kato, Riet Somers, Ludwine Messiaen, Sofie De Schepper, Jean Pierre Fryns, Jan Cools, Peter Marynen, Gilles Thomas, Akihiko Yoshimura, Eric Legius

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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 family of proteins that act as negative regulators of RAS->RAF interaction and mitogen-activated protein kinase (MAPK) signaling. 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 pathway. To our knowledge, this is the first report of mutations in the SPRY (SPROUTY)/SPRED family of genes in human disease.

Original languageEnglish
Pages (from-to)1120-1126
Number of pages7
JournalNature genetics
Volume39
Issue number9
DOIs
Publication statusPublished - 2007 Sep 1
Externally publishedYes

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ASJC Scopus subject areas

  • Genetics

Cite this

Brems, H., Chmara, M., Sahbatou, M., Denayer, E., Taniguchi, K., Kato, R., Somers, R., Messiaen, L., De Schepper, S., Fryns, J. P., Cools, J., Marynen, P., Thomas, G., Yoshimura, A., & Legius, E. (2007). Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nature genetics, 39(9), 1120-1126. https://doi.org/10.1038/ng2113