HGNC Approved Gene Symbol: SPRED1
SNOMEDCT: 703541007;
Cytogenetic location: 15q14 Genomic coordinates (GRCh38): 15:38,252,836-38,357,249 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q14 | Legius syndrome | 611431 | Autosomal dominant | 3 |
SPRED1 is a member of the Sprouty (see SPRY1; 602465)/SPRED family of proteins that regulate growth factor-induced activation of the MAP kinase cascade (see MAPK1, 176948) (Nonami et al., 2004).
Wakioka et al. (2001) cloned mouse Spred1 from an osteoclast cDNA library. The deduced 444-amino acid protein contains an N-terminal Enabled (ENA; 609061)/VASP (601703) homology-1 (EVH1) domain, a central KIT (164920)-binding domain (KBD), and a C-terminal SPRY domain.
Using Northern blot analysis, Kato et al. (2003) detected Spred1 expression in mouse brain, kidney, and colon, but not in any other tissues examined. Nonami et al. (2004) found Spred1 highly expressed in interleukin-3 (IL3; 147740)-dependent mouse hematopoietic cell lines and bone marrow-derived mast cells.
The SPRED1 protein has a molecular mass of 50 kD and contains 444 amino acids (review by Brems et al., 2012).
Brems et al. (2007) noted that the SPRED1 gene contains 8 exons.
By genomic sequence analysis, Kato et al. (2003) mapped the SPRED1 gene to chromosome 15q13.2. They mapped the mouse Spred1 gene to chromosome 2E5 using FISH.
Wakioka et al. (2001) found that mammalian Spred1 was phosphorylated in response to several growth factors, and efficient phosphorylation required the KBD domain. Overexpression of Spred1 inhibited NGF (162030)-induced neurite differentiation in rat PC12 cells, and both the EVH1 and SPRY domains were essential for the suppression. Wakioka et al. (2001) presented evidence that Spred1 and Spred2 (609292) could regulate differentiation in rat neuronal cells and mouse myocytes by inhibiting activation of MAP kinase. Inhibition appeared to occur through the formation of a Spred-Ras (190020) complex that inhibited activation of MAP kinase by suppressing phosphorylation and activation of Raf (see RAF1; 164760).
Kato et al. (2003) found that mouse Spred1 coprecipitated with and was phosphorylated by a constitutively activated Kit mutant. The KBD was required for Kit binding, but suppression of growth factor-induced MAP kinase required the SPRY domain.
Nonami et al. (2004) found that mouse Spred1 negatively regulated hematopoiesis by suppressing stem cell factor (KITLG; 184745)- and IL3-induced ERK (see MAPK3; 601795) activation.
MicroRNAs, such as MIR126 (611767), downregulate mRNA expression by binding to short complementary sequences in the 3-prime UTRs of target mRNAs. Wang et al. (2008) found that knockout of Mir126 in mice caused severe defects in vascularization. Using microarray analysis, they showed that endothelial cells from Mir126 -/- kidneys had elevated levels of Spred1, as well as numerous other genes involved in angiogenesis, cell adhesion, inflammatory/cytokine signaling, and cell cycle control. Real-time PCR and Western blot analysis confirmed upregulation of Spred1 in Mir126 -/- endothelial cells. Wang et al. (2008) identified a sequence complementary to the seed sequence of Mir126 in the 3-prime UTR of Spred1 mRNA, and they confirmed that Mir126 downregulated expression of a reporter gene that included the Spred1 3-prime UTR. Further experiments revealed that Mir126 augmented angiogenesis by diminishing the inhibitory influence of Spred1 on the MAP kinase pathway.
Hollander et al. (2010) found that miR212 (613487) was upregulated in the dorsal striatum of rats with a history of extended access to cocaine. Striatal miR212 decreased responsiveness to the motivational properties of cocaine by markedly amplifying the stimulatory effects of the drug on Creb (123810) signaling. Studies in rats and HEK cells showed that amplification of CREB signaling occurred through miR212-enhanced RAF1 activity, resulting in adenylyl cyclase sensitization and increased expression of the essential Creb coactivator TORC (see CRTC1; 607536). miR212 activated RAF1, at least in part, through repression of SPRED1. Hollander et al. (2010) concluded that striatal miR212 signaling has a key role in determining vulnerability to cocaine addiction.
To identify driver genes in mucosal melanoma, Ablain et al. (2018) sequenced hundreds of cancer-related genes in 43 human mucosal melanomas (see 155600), cataloging point mutations, amplifications, and deletions. The SPRED1 gene, which encodes a negative regulator of mitogen-activated protein kinase (MAPK) signaling, was inactivated in 37% of the tumors. Four distinct genotypes were associated with SPRED1 loss. Using a rapid, tissue-specific CRISPR technique to model these genotypes in zebrafish, Ablain et al. (2018) found that SPRED1 functions as a tumor suppressor, particularly in the context of KIT (164920) mutations. SPRED1 knockdown caused MAPK activation, increased cell proliferation, and conferred resistance to drugs inhibiting KIT tyrosine kinase activity.
In a review of the molecular genetics of Legius syndrome (LGSS; 611431), Brems et al. (2012) noted that SPRED1 mutations result in a loss of protein function and an inability of SPRED1 to downregulate the RAS-MAPK pathway. There are no apparent genotype/phenotype correlations.
In affected members of 5 unrelated families with Legius syndrome, Brems et al. (2007) identified 4 different heterozygous mutations in the SPRED1 gene (609291.0001-609291.0004). Screening of 86 additional patients who had undergone NF1 (162200) testing with negative results identified 7 additional SPRED1 mutations (see, e.g., 609291.0005). Melanocyte culture studies demonstrated that SPRED1 -/- cells had higher MAPK and ERK phosphorylation compared to heterozygous or wildtype cells. Further studies indicated that the mutations resulted in loss of function and that mutant SPRED1 proteins had lost their ability to inhibit RAF-MEK (see 176872)-ERK signaling. Haploinsufficiency appeared to be the mechanism.
Pasmant et al. (2009) identified 5 truncating mutations in the SPRED1 gene (see, e.g., 609291.0005 and 609291.0006) in affected members of 5 unrelated French families with Legius syndrome. The phenotype included a high prevalence of cafe-au-lait spots and axillary and groin freckling. Other variable features included lipomas and learning disabilities. Facial dysmorphism was not observed. As none of the patients had neurofibromas or Lisch nodules, Pasmant et al. (2009) suggested that the condition be named 'Legius syndrome.'
Spurlock et al. (2009) identified 6 different SPRED1 mutations (see, e.g., 609291.0007 and 609291.0008) in 6 of 85 probands with a mild NF1 phenotype and no neurofibromas.
Laycock-van Spyk et al. (2011) identified 6 different heterozygous nonsense or frameshift mutations in the SPRED1 gene in 6 of 115 patients with an NF1-like syndrome but without mutations in the NF1 gene. Combining their data with those from their earlier study (Spurlock et al., 2009), Laycock-van Spyk et al. (2011) estimated that SPRED1 mutations are found in about 6% of such patients.
Spencer et al. (2011) used multiplex ligation-dependent probe amplification (MLPA) to screen 510 NF1-negative patients with multiple cafe-au-lait spots with or without freckling and no other signs of NF1 for deletions in the SPRED1 gene. Four different deletions were detected, including 2 that segregated with the phenotype in 2 families and 2 that were apparently sporadic. All the deletions had different breakpoints, with 1 including 2 neighboring genes. Point mutations or 1- to 4-bp insertion/deletion mutations were found in 36 of the 510 individuals. Thus, deletions accounted for about 10% of the 40 detected SPRED1 mutations in this cohort, suggesting that dosage analysis of this gene should be performed in candidate patients.
Inoue et al. (2005) generated healthy and fertile Spred1-deficient mice by targeting exons encoding the KIT-binding and Sprouty-related domains. Spred1-deficient mice showed exaggerated allergen-induced airway hyperresponsiveness, eosinophilia, and mucus production in an allergic asthma model. They also had increased responsiveness, in terms of ERK signaling, to Il5 (147850) with subsequent overexpression of Il13 (147683) in eosinophils. Inoue et al. (2005) proposed that SPRED1 downregulation in the airway has a role in prolonged airway eosinophilia and asthma phenotypes.
In affected members of 2 unrelated families with autosomal dominant Legius syndrome (LGSS; 611431), Brems et al. (2007) identified a heterozygous 349C-T transition in exon 4 of the SPRED1 gene, resulting in an arg117-to-ter (R117X) substitution.
In affected members of a family with Legius syndrome (LGSS; 611431), Brems et al. (2007) identified a heterozygous 70C-T transition in exon 3 of the SPRED1 gene, resulting in an arg24-to-ter (R24X) substitution. The R24X mutation was present in normal skin and melanocytes from a cafe-au-lait spot of 1 patient, but melanocytes from the cafe-au-lait spot showed an additional somatic SPRED1 mutation. The 2 mutations were located on different alleles, suggesting that SPRED1 function was completely absent in these cells.
In affected members of a family with Legius syndrome (LGSS; 611431), Brems et al. (2007) identified a heterozygous G-to-A transition in the donor splice site of intron 5 (423+1G-A), resulting in the skipping of exon 5 and an out-of-frame deletion of 47 nucleotides at the mRNA level.
In affected members of a family with Legius syndrome (LGSS; 611431), Brems et al. (2007) identified a heterozygous 643C-T transition in exon 7 of the SPRED1 gene, resulting in a gln215-to-ter (Q215X) substitution.
In an individual with Legius syndrome (LGSS; 611431), Brems et al. (2007) identified a heterozygous 190C-T transition in exon 3 of the SPRED1 gene, resulting in an arg64-to-ter (R64X) substitution. The patient had multiple cafe-au-lait spots and did not have a NF1 mutation.
In affected members of a French family with Legius syndrome, Pasmant et al. (2009) identified the same R64X mutation. The phenotype included a high prevalence of cafe-au-lait spots and axillary and groin freckling. Two patients had a lipoma and another had learning disability. None had neurofibromas or Lisch nodules.
In affected members of a French family with Legius syndrome (LGSS; 611431), Pasmant et al. (2009) identified a heterozygous 637C-T transition in exon 7 of the SPRED1 gene, resulting in a gln213-to-ter (Q213X) substitution. The phenotype included a high prevalence of cafe-au-lait spots and axillary and groin freckling. One patient had a learning disability. None had neurofibromas or Lisch nodules.
In a father and son with Legius syndrome (LGSS; 611431), Spurlock et al. (2009) identified a heterozygous 784A-T transversion in exon 8 of the SPRED1 gene, resulting in an arg262-to-ter (R262X) substitution. Both had cafe-au-lait spots and axillary freckling, but no neurofibromas.
In 4 affected members of a 3-generation family with Legius syndrome (LGSS; 611431), Spurlock et al. (2009) identified a heterozygous 131T-A transversion in exon 3 of the SPRED1 gene, resulting in a val44-to-asp (V55D) substitution in a highly conserved residue. All had cafe-au-lait spots, but no neurofibromas. The father had a head circumference in the 90th percentile, but all other family members had a normal head size.
In a mother and her 4 children, all with Legius syndrome (LGSS; 611431), Laycock-van Spyk et al. (2011) identified a heterozygous 2-bp deletion (1045delAG) in exon 7 of the SPRED1 gene, resulting in a frameshift and premature termination. The mother had perioral and ocular hyperpigmentation, hypertelorism, mild ptosis, and hypotonia. All patients had decreased IQ or learning difficulties. None had Lisch nodules or neurofibromas.
Ablain, J., Xu, M., Rothschild, H., Jordan, R. C., Mito, J. K., Daniels, B. H., Bell, C. F., Joseph, N. M., Wu, H., Bastian, B. C., Zon, L. I., Yeh, I. Human tumor genomics and zebrafish modeling identify SPRED1 loss as a driver of mucosal melanoma. Science 362: 1055-1060, 2018. [PubMed: 30385465] [Full Text: https://doi.org/10.1126/science.aau6509]
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. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. (Letter) Nature Genet. 39: 1120-1126, 2007. [PubMed: 17704776] [Full Text: https://doi.org/10.1038/ng2113]
Brems, H., Pasmant, E., Van Minkelen, R., Wimmer, K., Upadhyaya, M., Legius, E., Messiaen, L. Review and update of SPRED1 mutations causing Legius syndrome. Hum. Mutat. 33: 1538-1546, 2012. [PubMed: 22753041] [Full Text: https://doi.org/10.1002/humu.22152]
Hollander, J. A., Im, H.-I., Amelio, A. L., Kocerha, J., Bali, P., Lu, Q., Willoughby, D., Wahlestedt, C., Conkright, M. D., Kenny, P. J. Striatal microRNA controls cocaine intake through CREB signalling. Nature 466: 197-202, 2010. [PubMed: 20613834] [Full Text: https://doi.org/10.1038/nature09202]
Inoue, H., Kato, R., Fukuyama, S., Nonami, A., Taniguchi, K., Matsumoto, K., Nakano, T., Tsuda, M., Matsumura, M., Kubo, M., Ishikawa, F., Moon, B., Takatsu, K., Nakanishi, Y., Yoshimura, A. Spred-1 negatively regulates allergen-induced airway eosinophilia and hyperresponsiveness. J. Exp. Med. 201: 73-82, 2005. [PubMed: 15630138] [Full Text: https://doi.org/10.1084/jem.20040616]
Kato, R., Nonami, A., Taketomi, T., Wakioka, T., Kuroiwa, A., Matsuda, Y., Yoshimura, A. Molecular cloning of mammalian Spred-3 which suppresses tyrosine kinase-mediated Erk activation. Biochem. Biophys. Res. Commun. 302: 767-772, 2003. [PubMed: 12646235] [Full Text: https://doi.org/10.1016/s0006-291x(03)00259-6]
Laycock-van Spyk, S., Jim, H. P., Thomas, L., Spurlock, G., Fares, L., Palmer-Smith, S., Kini, U., Saggar, A., Patton, M., Mautner, V., Pilz, D. T., Upadhyaya, M. Identification of five novel SPRED1 germline mutations in Legius syndrome. (Letter) Clin. Genet. 80: 93-96, 2011. [PubMed: 21649642] [Full Text: https://doi.org/10.1111/j.1399-0004.2010.01618.x]
Nonami, A., Kato, R., Taniguchi, K., Yoshiga, D., Taketomi, T., Fukuyama, S., Harada, M., Sasaki, A., Yoshimura, A. Spred-1 negatively regulates interleukin-3-mediated ERK/mitogen-activated protein (MAP) kinase activation in hematopoietic cells. J. Biol. Chem. 279: 52543-52551, 2004. [PubMed: 15465815] [Full Text: https://doi.org/10.1074/jbc.M405189200]
Pasmant, E., Sabbagh, A., Hanna, N., Masliah-Planchon, J., Jolly, E., Goussard, P., Ballerini, P., Cartault, F., Barbarot, S., Landman-Parker, J., Soufir, N., Parfait, B., Vidaud, M., Wolkenstein, P., Vidaud, D., France, R. N. F. SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype. J. Med. Genet. 46: 425-430, 2009. [PubMed: 19366998] [Full Text: https://doi.org/10.1136/jmg.2008.065243]
Spencer, E., Davis, J., Mikhail, F., Fu, C., Vijzelaar, R., Zackai, E. H., Feret, H., Meyn, M. S., Shugar, A., Bellus, G., Kocsis, K., Kivirikko, S., Poyhonen, M., Messiaen, L. Identification of SPRED1 deletions using RT-PCR, multiplex ligation-dependent probe amplification and quantitative PCR. Am. J. Med. Genet. 155A: 1352-1359, 2011. [PubMed: 21548021] [Full Text: https://doi.org/10.1002/ajmg.a.33894]
Spurlock, G., Bennett, E., Chuzhanova, N., Thomas, N., Jim, H.-P., Side, L., Davies, S., Haan, E., Kerr, B., Huson, S. M., Upadhyaya, M. SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the neurofibromatosis type 1 phenotype. J. Med. Genet. 46: 431-437, 2009. [PubMed: 19443465] [Full Text: https://doi.org/10.1136/jmg.2008.065474]
Wakioka, T., Sasaki, A., Kato, R., Shouda, T., Matsumoto, A., Miyoshi, K., Tsuneoka, M., Komiya, S., Baron, R., Yoshimura, A. Spred is a Sprouty-related suppressor of Ras signalling. Nature 412: 647-651, 2001. [PubMed: 11493923] [Full Text: https://doi.org/10.1038/35088082]
Wang, S., Aurora, A. B., Johnson, B. A., Qi, X., McAnally, J., Hill, J. A., Richardson, J. A., Bassel-Duby, R., Olson, E. N. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev. Cell 15: 261-271, 2008. [PubMed: 18694565] [Full Text: https://doi.org/10.1016/j.devcel.2008.07.002]