SPRED1-gene

The SPRED1 gene (SPRED is the acronym for: Sprouty Related EVH1 Domain Containing 1) is a protein-coding gene located on chromosome 15q14. The protein encoded by this gene is a member of the Sprouty protein family and is phosphorylated by tyrosine kinase in response to various growth factors. The encoded protein can act as a homodimer or as a heterodimer with SPRED2 to regulate activation of the MAP kinase cascade.

SPRED1 mutations can lead to overactivation of the RAS-MAPK signal transduction cascade. Mutations are causative for Legius syndrome, also known as neurofibromatosis type 1-like syndrome (NFLS). Furthermore, they are associated withchildhood leukemia. Related signaling pathways include RET signaling and signaling through GPCR. An important paralog of this gene is SPRED2.

All mutations have now been entered into a database created using the Leiden Open Variation Database software, which is accessible at http://www.lovd.nl/SPRED1. Currently, the database contains 89 different mutations identified in 146 unrelated individuals, including 16 new variants described for the first time. The database contains a range of mutations: 29 missense, 28 frameshift, 19 nonsense, eight copy number variations, two splicing mutations, one silent mutation, one in-frame deletion, and one mutation affecting the initiation codon. 

63 mutations and deletions are definitively pathogenic or most likely pathogenic; 8 SPRED1 mutations are likely benign rare variants, and 17 SPRED1 missense mutations remain unclassified and require further family and functional studies to classify them definitively. Most pathogenic variants lead to premature translational termination during protein biosynthesis and to loss of function of the protein in inhibiting Raf1 kinase activation.