title: Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype.
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.
authors: Department of Human Genetics, Catholic University Leuven, 3000 Leuven, Belgium.
authors: Hilde
authors: H
authors: Brems
authors: Magdalena
authors: M
authors: Chmara
authors: Mourad
authors: M
authors: Sahbatou
authors: Ellen
authors: E
authors: Denayer
authors: Koji
authors: K
authors: Taniguchi
authors: Reiko
authors: R
authors: Kato
authors: Riet
authors: R
authors: Somers
authors: Ludwine
authors: L
authors: Messiaen
authors: Sofie
authors: S
authors: De Schepper
authors: Jean-Pierre
authors: JP
authors: Fryns
authors: Jan
authors: J
authors: Cools
authors: Peter
authors: P
authors: Marynen
authors: Gilles
authors: G
authors: Thomas
authors: Akihiko
authors: A
authors: Yoshimura
authors: Eric
authors: E
authors: Legius
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D018095:Germ-Line Mutation; D006801:Humans; D015151:Immunoblotting; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010375:Pedigree; D010641:Phenotype; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D018631:ras Proteins / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C504812:SPRED1 protein, human; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins