SPRED1

Last updated on: 22.07.2021

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Definition
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SPRED1 is a member of the so-called Sprouty (SPRY) family, a group of proteins that act as negative regulators within mitogen-activated protein kinase (MAPK) signal transduction.

General information
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SPRED1 (Sprouty-Related EVH1 Domain Containing 1) loss-of-function mutations in the germline can lead to overactivation of the MAP kinase signaling pathway.

Mutations are causative for Legius syndrome which is also known as neurofibromatosis type 1-like syndrome (NFLS). Furthermore, they are associated with childhood leukemia.

Ablain J et al (2021) identified SPRED1 as a novel tumor suppressor in KIT-driven melanomas. They demonstrated that SPRED1 is also frequently deleted in human melanomas driven by mutant BRAF. Mechanistically, loss of SPRED1 promoted proliferation of melanoma cells under inhibition of BRAF mutant by reactivation of MAPK activity.

Note(s)
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All mutations have now been deposited in a database created with the Leiden Open Variation Database software and accessible at http://www.lovd.nl/SPRED1. Currently, the database contains 89 different mutations identified in 146 unrelated probands, including 16 new variants described for the first time. The database contains a spectrum of mutations: 29 missense, 28 frameshift, 19 nonsense, eight copy number changes, two splice, one silent, one in-frame deletion and one mutation affecting the initiation codon. Sixty-three mutations and deletions are definitely pathogenic or most likely pathogenic, eight SPRED1 mutations are likely benign rare variants, and 17 SPRED1 missense mutations are not yet classified and need further family and functional studies to classify them with confidence. Most pathogenic variants result in premature translational arrest in protein biosynthesis and loss of protein function upon inhibition of Raf1 kinase activation.

Literature
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  1. Ablain J et al (2021) SPRED1 deletion confers resistance to MAPK inhibition in melanoma. J Exp Med 218:e20201097.
  2. Brems H et al (2012) Review and update of SPRED1 mutations causing Legius syndrome. Hum Mutat 33:1538-1546.
  3. Inoue H et al (2005) Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness. J Exp Med 201: 73-82
  4. Kato R et al. (2003) Molecular cloning of mammalian Spred-3 which suppresses tyrosine kinase-mediated Erk activation. Biochem Biophys Re. Commu. 302: 767-772.
  5. Pasmant E et al. (2015) Neurofibromatosis type 1 molecular diagnosis: what can NGS do for you when you have a large gene with loss of function mutations? Eur J Hum Genet 23:596-601.
  6. Tucci A et al (2017) The absence that makes the difference: choroidal abnormalities in Legius syndrome. J Hum Genet 62:1001-1004

Last updated on: 22.07.2021