SPRED1 explained

Sprouty-related, EVH1 domain-containing protein 1 (Spread-1) is a protein that in humans is encoded by the SPRED1 gene located on chromosome 15q13.2 and has seven coding exons.^[1]

Function

SPRED-1 is a member of the Sprouty family of proteins and is phosphorylated by tyrosine kinase in response to several growth factors. The encoded protein can act as a homodimer or as a heterodimer with SPRED2 to regulate activation of the MAP kinase cascade.^[1]

Clinical associations

Defects in this gene are a cause of neurofibromatosis type 1-like syndrome (NFLS).^[1]

Mutations in this gene are associated with

• Legius syndrome.^{[2] [3]}
• Childhood leukemia^[4]

Mutations

The following mutations have been observed:

• An exon 3 c.46C>T mutation leading to p.Arg16Stop.^[4] This mutation may result in a truncated nonfunctional protein. Blast cells analysis displayed the same abnormality as germline mutation with one mutated allele (no somatic SPRED1 single-point mutation or loss of heterozygosity was found). The M4/M5 phenotype of AML are most closely associated with Ras pathway mutations. Ras pathway mutations are also associated with monosomy 7.
• 3 Nonsense (R16X, E73X, R262X)^[5]
• 2 Frameshift (c.1048_c1049 delGG, c.149_1152del 4 bp)^[5]
• Missense (V44D)^[5]
• p.R18X and p.Q194X with phenotype altered pigmentation without tumoriginesis.^[6]

Disease Database

SPRED1 gene variant database

See also

• Neurofibromin 1
• Patients without Neurofibromin 1 or SPRED1 mutations may have SPRED2, SPRED3 or SPRY1, SPRY2, SPRY3 or SPRY4 mutations.^[5]

Further reading

• Batz C, Hasle H, Bergsträsser E, van den Heuvel-Eibrink MM, Zecca M, Niemeyer CM, Flotho C . Does SPRED1 contribute to leukemogenesis in juvenile myelomonocytic leukemia (JMML)? . Blood . 115 . 12 . 2557–8 . March 2010 . 20339110 . 10.1182/blood-2009-12-260901 .
• Lock P, I ST, Straffon AF, Schieb H, Hovens CM, Stylli SS . Spred-2 steady-state levels are regulated by phosphorylation and Cbl-mediated ubiquitination . Biochemical and Biophysical Research Communications . 351 . 4 . 1018–23 . December 2006 . 17094949 . 10.1016/j.bbrc.2006.10.150 .
• 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 RN . SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype . Journal of Medical Genetics . 46 . 7 . 425–30 . July 2009 . 19366998 . 10.1136/jmg.2008.065243 . 21323989 . free .
• Nonami A, Taketomi T, Kimura A, Saeki K, Takaki H, Sanada T, Taniguchi K, Harada M, Kato R, Yoshimura A . The Sprouty-related protein, Spred-1, localizes in a lipid raft/caveola and inhibits ERK activation in collaboration with caveolin-1 . Genes to Cells . 10 . 9 . 887–95 . September 2005 . 16115197 . 10.1111/j.1365-2443.2005.00886.x . free .
• Szafranski K, Schindler S, Taudien S, Hiller M, Huse K, Jahn N, Schreiber S, Backofen R, Platzer M . Violating the splicing rules: TG dinucleotides function as alternative 3' splice sites in U2-dependent introns . Genome Biology . 8 . 8 . R154 . 2007 . 17672918 . 2374985 . 10.1186/gb-2007-8-8-r154 . free .
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes . Genome Research . 16 . 1 . 55–65 . January 2006 . 16344560 . 1356129 . 10.1101/gr.4039406 .
• Chandramouli S, Yu CY, Yusoff P, Lao DH, Leong HF, Mizuno K, Guy GR . Tesk1 interacts with Spry2 to abrogate its inhibition of ERK phosphorylation downstream of receptor tyrosine kinase signaling . The Journal of Biological Chemistry . 283 . 3 . 1679–91 . January 2008 . 17974561 . 10.1074/jbc.M705457200 . free.
• Johne C, Matenia D, Li XY, Timm T, Balusamy K, Mandelkow EM . Spred1 and TESK1--two new interaction partners of the kinase MARKK/TAO1 that link the microtubule and actin cytoskeleton . Molecular Biology of the Cell . 19 . 4 . 1391–403 . April 2008 . 18216281 . 2291396 . 10.1091/mbc.E07-07-0730 .
• 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 . The Journal of Biological Chemistry . 279 . 50 . 52543–51 . December 2004 . 15465815 . 10.1074/jbc.M405189200 . free .
• Talmud PJ, Drenos F, Shah S, Shah T, Palmen J, Verzilli C, Gaunt TR, Pallas J, Lovering R, Li K, Casas JP, Sofat R, Kumari M, Rodriguez S, Johnson T, Newhouse SJ, Dominiczak A, Samani NJ, Caulfield M, Sever P, Stanton A, Shields DC, Padmanabhan S, Melander O, Hastie C, Delles C, Ebrahim S, Marmot MG, Smith GD, Lawlor DA, Munroe PB, Day IN, Kivimaki M, Whittaker J, Humphries SE, Hingorani AD . Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip . American Journal of Human Genetics . 85 . 5 . 628–42 . November 2009 . 19913121 . 2775832 . 10.1016/j.ajhg.2009.10.014 .
• Colland F, Jacq X, Trouplin V, Mougin C, Groizeleau C, Hamburger A, Meil A, Wojcik J, Legrain P, Gauthier JM . Functional proteomics mapping of a human signaling pathway . Genome Research . 14 . 7 . 1324–32 . July 2004 . 15231748 . 442148 . 10.1101/gr.2334104 .
• Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R, Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimura A, Legius E . Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype . Nature Genetics . 39 . 9 . 1120–6 . September 2007 . 17704776 . 10.1038/ng2113 . 35709088 .
• Yoshida T, Hisamoto T, Akiba J, Koga H, Nakamura K, Tokunaga Y, Hanada S, Kumemura H, Maeyama M, Harada M, Ogata H, Yano H, Kojiro M, Ueno T, Yoshimura A, Sata M . Spreds, inhibitors of the Ras/ERK signal transduction, are dysregulated in human hepatocellular carcinoma and linked to the malignant phenotype of tumors . Oncogene . 25 . 45 . 6056–66 . October 2006 . 16652141 . 10.1038/sj.onc.1209635 . 22188239 .
• King JA, Straffon AF, D'Abaco GM, Poon CL, I ST, Smith CM, Buchert M, Corcoran NM, Hall NE, Callus BA, Sarcevic B, Martin D, Lock P, Hovens CM . Distinct requirements for the Sprouty domain for functional activity of Spred proteins . The Biochemical Journal . 388 . Pt 2 . 445–54 . June 2005 . 15683364 . 1138951 . 10.1042/BJ20041284 .
• Bailey SD, Xie C, Do R, Montpetit A, Diaz R, Mohan V, Keavney B, Yusuf S, Gerstein HC, Engert JC, Anand S . Variation at the NFATC2 locus increases the risk of thiazolidinedione-induced edema in the Diabetes REduction Assessment with ramipril and rosiglitazone Medication (DREAM) study . Diabetes Care . 33 . 10 . 2250–3 . October 2010 . 20628086 . 2945168 . 10.2337/dc10-0452 .

Notes and References

1. Web site: Entrez Gene: sprouty-related.
2. Messiaen L, Yao S, Brems H, Callens T, Sathienkijkanchai A, Denayer E, Spencer E, Arn P, Babovic-Vuksanovic D, Bay C, Bobele G, Cohen BH, Escobar L, Eunpu D, Grebe T, Greenstein R, Hachen R, Irons M, Kronn D, Lemire E, Leppig K, Lim C, McDonald M, Narayanan V, Pearn A, Pedersen R, Powell B, Shapiro LR, Skidmore D, Tegay D, Thiese H, Zackai EH, Vijzelaar R, Taniguchi K, Ayada T, Okamoto F, Yoshimura A, Parret A, Korf B, Legius E . Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome . JAMA . 302 . 19 . 2111–8 . November 2009 . 19920235 . 10.1001/jama.2009.1663 .
   • Web site: Allison Gandey . November 18, 2009 . Legius Syndrome Often Mistaken for Neurofibromatosis Type 1 . Medscape .
3. Web site: Legius Syndrome (SPRED1) Sequencing & (NF1) Sequencing Exon 22 (Exon 17) . 2010 . . 2011-06-07 . 2012-05-30 . https://web.archive.org/web/20120530015104/http://www.aruplab.com/Testing-Information/resources/TechnicalBulletins/Legius%20Syndrome%20%28SPRED1%29%20Sequencing%20%26%20%28NF1%29%20Sequencing%20Exon%2022%20%28Exon%2017%29.pdf . dead .
4. Pasmant E, Ballerini P, Lapillonne H, Perot C, Vidaud D, Leverger G, Landman-Parker J . SPRED1 disorder and predisposition to leukemia in children . Blood . 114 . 5 . 1131 . July 2009 . 19643996 . 10.1182/blood-2009-04-218503 . free .
5. Spurlock G, Bennett E, Chuzhanova N, Thomas N, Jim HP, Side L, Davies S, Haan E, Kerr B, Huson SM, Upadhyaya M . SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the neurofibromatosis type 1 phenotype . Journal of Medical Genetics . 46 . 7 . 431–7 . July 2009 . 19443465 . 10.1136/jmg.2008.065474 . free .
6. Muram-Zborovski TM, Stevenson DA, Viskochil DH, Dries DC, Wilson AR . SPRED 1 mutations in a neurofibromatosis clinic . Journal of Child Neurology . 25 . 10 . 1203–9 . October 2010 . 20179001 . 3243064 . 10.1177/0883073809359540 .