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

Nat Genet. 2007 Sep;39(9):1120-6. doi: 10.1038/ng2113. Epub 2007 Aug 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Analysis of Variance
  • Cell Line
  • Child
  • Child, Preschool
  • DNA Mutational Analysis
  • Female
  • Germ-Line Mutation*
  • Humans
  • Immunoblotting
  • Infant
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / physiology
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / physiology
  • Middle Aged
  • Mitogen-Activated Protein Kinases / metabolism
  • Neurofibromatosis 1 / genetics*
  • Neurofibromatosis 1 / metabolism
  • Neurofibromatosis 1 / pathology*
  • Pedigree
  • Phenotype
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • ras Proteins / metabolism

Substances

  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • SPRED1 protein, human
  • Mitogen-Activated Protein Kinases
  • ras Proteins