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PDGF receptor mutations in human diseases

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Abstract

PDGFRA and PDGFRB are classical proto-oncogenes that encode receptor tyrosine kinases responding to platelet-derived growth factor (PDGF). PDGFRA mutations are found in gastrointestinal stromal tumors (GISTs), inflammatory fibroid polyps and gliomas, and PDGFRB mutations drive myofibroma development. In addition, chromosomal rearrangement of either gene causes myeloid neoplasms associated with hypereosinophilia. Recently, mutations in PDGFRB were linked to several noncancerous diseases. Germline heterozygous variants that reduce receptor activity have been identified in primary familial brain calcification, whereas gain-of-function mutants are present in patients with fusiform aneurysms, Kosaki overgrowth syndrome or Penttinen premature aging syndrome. Functional analysis of these variants has led to the preclinical validation of tyrosine kinase inhibitors targeting PDGF receptors, such as imatinib, as a treatment for some of these conditions. This review summarizes the rapidly expanding knowledge in this field.

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References

  1. Demoulin JB, Essaghir A (2014) PDGF receptor signaling networks in normal and cancer cells. Cytokine Growth Factor Rev 25(3):273–283. https://doi.org/10.1016/j.cytogfr.2014.03.003

    Article  CAS  PubMed  Google Scholar 

  2. Andrae J, Gallini R, Betsholtz C (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22(10):1276–1312. https://doi.org/10.1101/gad.1653708

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Heldin CH, Westermark B (1999) Mechanism of action and in vivo role of platelet-derived growth factor. Physiol Rev 79(4):1283–1316

    Article  CAS  PubMed  Google Scholar 

  4. Hoch RV, Soriano P (2003) Roles of PDGF in animal development. Development 130(20):4769–4784. https://doi.org/10.1242/dev.00721

    Article  CAS  PubMed  Google Scholar 

  5. Verstraete K, Savvides SN (2012) Extracellular assembly and activation principles of oncogenic class III receptor tyrosine kinases. Nat Rev Cancer 12(11):753–766. https://doi.org/10.1038/nrc3371

    Article  CAS  PubMed  Google Scholar 

  6. Liang L, Yan X-E, Yin Y, Yun C-H (2016) Structural and biochemical studies of the PDGFRA kinase domain. Biochem Biophys Res Commun 477(4):667–672. https://doi.org/10.1016/j.bbrc.2016.06.117

    Article  CAS  PubMed  Google Scholar 

  7. Hye-Ryong Shim A, Liu H, Focia PJ, Chen X, Lin PC, He X (2010) Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex. Proc Natl Acad Sci 107(25):11307. https://doi.org/10.1073/pnas.1000806107

    Article  PubMed  PubMed Central  Google Scholar 

  8. Chen PH, Unger V, He X (2015) Structure of full-length human PDGFRbeta bound to its activating ligand PDGF-B as determined by negative-stain electron microscopy. J Mol Biol 427(24):3921–3934. https://doi.org/10.1016/j.jmb.2015.10.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Beenstock J, Mooshayef N, Engelberg D (2016) How do protein kinases take a selfie (autophosphorylate)? Trends Biochem Sci 41(11):938–953. https://doi.org/10.1016/j.tibs.2016.08.006

    Article  CAS  PubMed  Google Scholar 

  10. Buhl EM, Djudjaj S, Klinkhammer BM, Ermert K, Puelles VG, Lindenmeyer MT, Cohen CD, He C, Borkham-Kamphorst E, Weiskirchen R, Denecke B, Trairatphisan P, Saez-Rodriguez J, Huber TB, Olson LE, Floege J, Boor P (2020) Dysregulated mesenchymal PDGFR-beta drives kidney fibrosis. EMBO Mol Med 12(3):e11021. https://doi.org/10.15252/emmm.201911021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang J, Yang PL, Gray NS (2009) Targeting cancer with small molecule kinase inhibitors. Nat Rev Cancer 9(1):28–39. https://doi.org/10.1038/nrc2559

    Article  CAS  PubMed  Google Scholar 

  12. Heldin C-H, Lennartsson J (2013) Structural and functional properties of platelet-derived growth factor and stem cell factor receptors. Cold Spring Harb Perspect Biol 5(8):a009100–a009100. https://doi.org/10.1101/cshperspect.a009100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lemmon MA, Schlessinger J (2010) Cell signaling by receptor tyrosine kinases. Cell 141(7):1117–1134. https://doi.org/10.1016/j.cell.2010.06.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ding H, Wu X, Bostrom H, Kim I, Wong N, Tsoi B, O’Rourke M, Koh GY, Soriano P, Betsholtz C, Hart TC, Marazita ML, Field LL, Tam PP, Nagy A (2004) A specific requirement for PDGF-C in palate formation and PDGFR-alpha signaling. Nat Genet 36(10):1111–1116. https://doi.org/10.1038/ng1415

    Article  CAS  PubMed  Google Scholar 

  15. Soriano P (1997) The PDGF alpha receptor is required for neural crest cell development and for normal patterning of the somites. Development 124(14):2691–2700

    Article  CAS  PubMed  Google Scholar 

  16. Lindahl P, Johansson BR, Leveen P, Betsholtz C (1997) Pericyte loss and microaneurysm formation in PDGF-B-deficient mice. Science 277(5323):242–245

    Article  CAS  PubMed  Google Scholar 

  17. Soriano P (1994) Abnormal kidney development and hematological disorders in PDGF beta-receptor mutant mice. Genes Dev 8(16):1888–1896

    Article  CAS  PubMed  Google Scholar 

  18. Gladh H, Folestad EB, Muhl L, Ehnman M, Tannenberg P, Lawrence AL, Betsholtz C, Eriksson U (2016) Mice lacking platelet-derived growth factor D display a mild vascular phenotype. PLoS ONE 11(3):e0152276. https://doi.org/10.1371/journal.pone.0152276

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lynch SE, Nixon JC, Colvin RB, Antoniades HN (1987) Role of platelet-derived growth factor in wound healing: synergistic effects with other growth factors. Proc Natl Acad Sci U S A 84(21):7696–7700. https://doi.org/10.1073/pnas.84.21.7696

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pierce GF, Mustoe TA, Altrock BW, Deuel TF, Thomason A (1991) Role of platelet-derived growth factor in wound healing. J Cell Biochem 45(4):319–326. https://doi.org/10.1002/jcb.240450403

    Article  CAS  PubMed  Google Scholar 

  21. Böhm AM, Dirckx N, Tower RJ, Peredo N, Vanuytven S, Theunis K, Nefyodova E, Cardoen R, Lindner V, Voet T, Van Hul M, Maes C (2019) Activation of skeletal stem and progenitor cells for bone regeneration is driven by PDGFRβ signaling. Dev Cell 51(2):236-254.e212. https://doi.org/10.1016/j.devcel.2019.08.013

    Article  CAS  PubMed  Google Scholar 

  22. Vishvanath L, MacPherson KA, Hepler C, Wang QA, Shao M, Spurgin SB, Wang MY, Kusminski CM, Morley TS, Gupta RK (2016) Pdgfrβ+ mural preadipocytes contribute to adipocyte hyperplasia induced by high-fat-diet feeding and prolonged cold exposure in adult mice. Cell Metab 23(2):350–359. https://doi.org/10.1016/j.cmet.2015.10.018

    Article  CAS  PubMed  Google Scholar 

  23. Yue Z, Chen J, Lian H, Pei J, Li Y, Chen X, Song S, Xia J, Zhou B, Feng J, Zhang X, Hu S, Nie Y (2019) PDGFR-β signaling regulates cardiomyocyte proliferation and myocardial regeneration. Cell Rep 28(4):966-978.e964. https://doi.org/10.1016/j.celrep.2019.06.065

    Article  CAS  PubMed  Google Scholar 

  24. Gullberg D, Tingström A, Thuresson A-C, Olsson L, Terracio L, Borg TK, Rubin K (1990) β1 Integrin-mediated collagen gel contraction is stimulated by PDGF. Exp Cell Res 186(2):264–272. https://doi.org/10.1016/0014-4827(90)90305-T

    Article  CAS  PubMed  Google Scholar 

  25. Heuchel R, Berg A, Tallquist M, Åhlén K, Reed RK, Rubin K, Claesson-Welsh L, Heldin C-H, Soriano P (1999) Platelet-derived growth factor β receptor regulates interstitial fluid homeostasis through phosphatidylinositol-3′ kinase signaling. Proc Natl Acad Sci 96(20):11410–11415. https://doi.org/10.1073/pnas.96.20.11410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Millot F, Guilhot J, Baruchel A, Petit A, Leblanc T, Bertrand Y, Mazingue F, Lutz P, Vérité C, Berthou C, Galambrun C, Sirvent N, Yacouben K, Chastagner P, Gandemer V, Reguerre Y, Couillault G, Khalifeh T, Rialland F (2014) Growth deceleration in children treated with imatinib for chronic myeloid leukaemia. Eur J Cancer 50(18):3206–3211. https://doi.org/10.1016/j.ejca.2014.10.007

    Article  CAS  PubMed  Google Scholar 

  27. Appiah-Kubi K, Lan T, Wang Y, Qian H, Wu M, Yao X, Wu Y, Chen Y (2017) Platelet-derived growth factor receptors (PDGFRs) fusion genes involvement in hematological malignancies. Crit Rev Oncol/Hematol 109:20–34. https://doi.org/10.1016/j.critrevonc.2016.11.008

    Article  Google Scholar 

  28. Havelange V, Demoulin JB (2013) Review of current classification, molecular alterations, and tyrosine kinase inhibitor therapies in myeloproliferative disorders with hypereosinophilia. J Blood Med 4:111–121. https://doi.org/10.2147/JBM.S33142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Medves S, Demoulin JB (2012) Tyrosine kinase gene fusions in cancer: translating mechanisms into targeted therapies. J Cell Mol Med 16(2):237–248. https://doi.org/10.1111/j.1582-4934.2011.01415.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Toffalini F, Demoulin J-B (2010) New insights into the mechanisms of hematopoietic cell transformation by activated receptor tyrosine kinases. Blood 116(14):2429–2437. https://doi.org/10.1182/blood-2010-04-279752

    Article  CAS  PubMed  Google Scholar 

  31. Demoulin JB, Montano-Almendras CP (2012) Platelet-derived growth factors and their receptors in normal and malignant hematopoiesis. Am J Blood Res 2(1):44–56

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Schwab C, Ryan SL, Chilton L, Elliott A, Murray J, Richardson S, Wragg C, Moppett J, Cummins M, Tunstall O, Parker CA, Saha V, Goulden N, Vora A, Moorman AV, Harrison CJ (2016) EBF1-PDGFRB fusion in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL): genetic profile and clinical implications. Blood 127(18):2214–2218. https://doi.org/10.1182/blood-2015-09-670166

    Article  CAS  PubMed  Google Scholar 

  33. Elling C, Erben P, Walz C, Frickenhaus M, Schemionek M, Stehling M, Serve H, Cross NC, Hochhaus A, Hofmann WK, Berdel WE, Muller-Tidow C, Reiter A, Koschmieder S (2011) Novel imatinib-sensitive PDGFRA-activating point mutations in hypereosinophilic syndrome induce growth factor independence and leukemia-like disease. Blood 117(10):2935–2943. https://doi.org/10.1182/blood-2010-05-286757

    Article  CAS  PubMed  Google Scholar 

  34. Li Z, Lan X, Li C, Zhang Y, Wang Y, Xue W, Lu L, Jin M, Zhou Z, Wang X, Li L, Zhang L, Li X, Fu X, Sun Z, Wu J, Zhang X, Yu H, Nan F, Chang Y, Yan J, Wu X, Wang G, Zhang D, Zhang Y, Young KH, Zhang M (2019) Recurrent PDGFRB mutations in unicentric Castleman disease. Leukemia 33(4):1035–1038. https://doi.org/10.1038/s41375-018-0323-6

    Article  PubMed  PubMed Central  Google Scholar 

  35. Onoufriadis A, Boulouadnine B, Dachy G, Higashino T, Huang HY, Hsu CK, Simpson MA, Bork K, Demoulin JB, McGrath J (2021) Germline mutation in PDGFRB may be implicated in hereditary progressive mucinous histiocytosis. Br J Dermatol (In press)

  36. Corless CL, Schroeder A, Griffith D, Town A, McGreevey L, Harrell P, Shiraga S, Bainbridge T, Morich J, Heinrich MC (2005) PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib. J Clin Oncol 23(23):5357–5364. https://doi.org/10.1200/JCO.2005.14.068

    Article  CAS  PubMed  Google Scholar 

  37. Lasota J, Stachura J, Miettinen M (2006) GISTs with PDGFRA exon 14 mutations represent subset of clinically favorable gastric tumors with epithelioid morphology. Laboratory investigation; a journal of technical methods and pathology 86 (1):94–100. doi:https://doi.org/10.1038/labinvest.3700360

  38. Huss S, Wardelmann E, Goltz D, Binot E, Hartmann W, Merkelbach-Bruse S, Buttner R, Schildhaus HU (2012) Activating PDGFRA mutations in inflammatory fibroid polyps occur in exons 12, 14 and 18 and are associated with tumour localization. Histopathology 61(1):59–68. https://doi.org/10.1111/j.1365-2559.2012.04203.x

    Article  PubMed  Google Scholar 

  39. Lasota J, Wang ZF, Sobin LH, Miettinen M (2009) Gain-of-function PDGFRA mutations, earlier reported in gastrointestinal stromal tumors, are common in small intestinal inflammatory fibroid polyps. A study of 60 cases. Modern pathology: an official journal of the United States and Canadian Academy of Pathology, Inc 22 (8):1049–1056. doi:https://doi.org/10.1038/modpathol.2009.62

  40. Chompret A, Kannengiesser C, Barrois M, Terrier P, Dahan P, Tursz T, Lenoir GM, Bressac-De Paillerets B (2004) PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology 126(1):318–321

    Article  CAS  PubMed  Google Scholar 

  41. Ricci R, Martini M, Cenci T, Carbone A, Lanza P, Biondi A, Rindi G, Cassano A, Larghi A, Persiani R, Larocca LM (2015) PDGFRA-mutant syndrome. Modern Pathology: an official journal of the United States and Canadian Academy of Pathology, Inc 28 (7):954–964. doi:https://doi.org/10.1038/modpathol.2015.56

  42. Carney JA, Stratakis CA (2008) Stromal, fibrous, and fatty gastrointestinal tumors in a patient with a PDGFRA gene mutation. Am J Surg Pathol 32(9):1412–1420. https://doi.org/10.1097/PAS.0b013e31816250ce

    Article  PubMed  PubMed Central  Google Scholar 

  43. Ricci R, Martini M, Cenci T, Riccioni ME, Maria G, Cassano A, Larocca LM (2016) Divergent gastrointestinal stromal tumors in syndromic settings. Cancer Genetics 209(7–8):354–358. https://doi.org/10.1016/j.cancergen.2016.05.073

    Article  CAS  PubMed  Google Scholar 

  44. Ozawa T, Brennan CW, Wang L, Squatrito M, Sasayama T, Nakada M, Huse JT, Pedraza A, Utsuki S, Yasui Y, Tandon A, Fomchenko EI, Oka H, Levine RL, Fujii K, Ladanyi M, Holland EC (2010) PDGFRA gene rearrangements are frequent genetic events in PDGFRA-amplified glioblastomas. Genes Dev 24(19):2205–2218. https://doi.org/10.1101/gad.1972310

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Paugh BS, Zhu X, Qu C, Endersby R, Diaz AK, Zhang J, Bax DA, Carvalho D, Reis RM, Onar-Thomas A, Broniscer A, Wetmore C, Zhang J, Jones C, Ellison DW, Baker SJ (2013) Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas. Cancer Res 73(20):6219–6229. https://doi.org/10.1158/0008-5472.CAN-13-1491

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ip CKM, Ng PKS, Jeong KJ, Shao SH, Ju Z, Leonard PG, Hua X, Vellano CP, Woessner R, Sahni N, Scott KL, Mills GB (2018) Neomorphic PDGFRA extracellular domain driver mutations are resistant to PDGFRA targeted therapies. Nat Commun 9(1):4583. https://doi.org/10.1038/s41467-018-06949-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Velghe AI, Van Cauwenberghe S, Polyansky AA, Chand D, Montano-Almendras CP, Charni S, Hallberg B, Essaghir A, Demoulin JB (2014) PDGFRA alterations in cancer: characterization of a gain-of-function V536E transmembrane mutant as well as loss-of-function and passenger mutations. Oncogene 33(20):2568–2576. https://doi.org/10.1038/onc.2013.218

    Article  CAS  PubMed  Google Scholar 

  48. Lapin DH, Tsoli M, Ziegler DS (2017) Genomic insights into diffuse intrinsic pontine glioma. Front Oncol 7:57–57. https://doi.org/10.3389/fonc.2017.00057

    Article  PubMed  PubMed Central  Google Scholar 

  49. Chiang JCH, Harreld JH, Tanaka R, Li X, Wen J, Zhang C, Boué DR, Rauch TM, Boyd JT, Chen J, Corbo JC, Bouldin TW, Elton SW, Liu LL, Schofield D, Lee SC, Bouffard JP, Georgescu MM, Dossani RH, Aguiar MA, Sances RA, Saad AG, Boop FA, Qaddoumi I, Ellison DW (2019) Septal dysembryoplastic neuroepithelial tumor: a comprehensive clinical, imaging, histopathologic, and molecular analysis. Neuro Oncol 21(6):800–808. https://doi.org/10.1093/neuonc/noz037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Lucas CG, Villanueva-Meyer JE, Whipple N, Oberheim Bush NA, Cooney T, Chang S, McDermott M, Berger M, Cham E, Sun PP, Putnam A, Zhou H, Bollo R, Cheshier S, Poppe MM, Fung KM, Sung S, Glenn C, Fan X, Bannykh S, Hu J, Danielpour M, Li R, Alva E, Johnston J, Van Ziffle J, Onodera C, Devine P, Grenert JP, Lee JC, Pekmezci M, Tihan T, Bollen AW, Perry A, Solomon DA (2020) Myxoid glioneuronal tumor, PDGFRA p.K385-mutant: clinical, radiologic, and histopathologic features. Brain pathology 30 (3):479–494. doi:https://doi.org/10.1111/bpa.12797

  51. Solomon DA, Korshunov A, Sill M, Jones DTW, Kool M, Pfister SM, Fan X, Bannykh S, Hu J, Danielpour M, Li R, Johnston J, Cham E, Cooney T, Sun PP, Oberheim Bush NA, McDermott M, Van Ziffle J, Onodera C, Grenert JP, Bastian BC, Villanueva-Meyer JE, Pekmezci M, Bollen AW, Perry A (2018) Myxoid glioneuronal tumor of the septum pellucidum and lateral ventricle is defined by a recurrent PDGFRA p.K385 mutation and DNT-like methylation profile. Acta Neuropathol 136 (2):339–343. doi:https://doi.org/10.1007/s00401-018-1883-2

  52. Flavahan WA, Drier Y, Liau BB, Gillespie SM, Venteicher AS, Stemmer-Rachamimov AO, Suvà ML, Bernstein BE (2016) Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature 529(7584):110–114. https://doi.org/10.1038/nature16490

    Article  CAS  PubMed  Google Scholar 

  53. Mashiah J, Hadj-Rabia S, Dompmartin A, Harroche A, Laloum-Grynberg E, Wolter M, Amoric J-C, Hamel-Teillac D, Guero S, Fraitag S, Bodemer C (2014) Infantile myofibromatosis: a series of 28 cases. J Am Acad Dermatol 71(2):264–270. https://doi.org/10.1016/j.jaad.2014.03.035

    Article  PubMed  Google Scholar 

  54. Cheung YH, Gayden T, Campeau PM, LeDuc CA, Russo D, Nguyen VH, Guo J, Qi M, Guan Y, Albrecht S, Moroz B, Eldin KW, Lu JT, Schwartzentruber J, Malkin D, Berghuis AM, Emil S, Gibbs RA, Burk DL, Vanstone M, Lee BH, Orchard D, Boycott KM, Chung WK, Jabado N (2013) A recurrent PDGFRB mutation causes familial infantile myofibromatosis. Am J Hum Genet 92(6):996–1000. https://doi.org/10.1016/j.ajhg.2013.04.026

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ito N, Watanabe S, Mishima H, Kinoshita A, Okada M, Moriuchi H, Yoshiura K-i (2019) A mutation in PDGFRB in a family with infantile myofibromatosis. Acta Medica Nagasakiensia 63(1):49–53. https://doi.org/10.11343/amn.63.49

    Article  CAS  Google Scholar 

  56. Lepelletier C, Al-Sarraj Y, Bodemer C, Shaath H, Fraitag S, Kambouris M, Hamel-Teillac D, El Shanti H, Hadj-Rabia S (2017) Heterozygous PDGFRB mutation in a three-generation family with autosomal dominant infantile myofibromatosis. Acta Derm Venereol 97(7):858–859. https://doi.org/10.2340/00015555-2671

    Article  PubMed  Google Scholar 

  57. Linhares ND, Freire MC, Cardenas RG, Bahia M, Puzenat E, Aubin F, Pena SD (2014) Modulation of expressivity in PDGFRB-related infantile myofibromatosis: a role for PTPRG? Genet Mol Res 13(3):6287–6292. https://doi.org/10.4238/2014.August.15.11

    Article  CAS  PubMed  Google Scholar 

  58. Martignetti JA, Tian L, Li D, Ramirez MC, Camacho-Vanegas O, Camacho SC, Guo Y, Zand DJ, Bernstein AM, Masur SK, Kim CE, Otieno FG, Hou C, Abdel-Magid N, Tweddale B, Metry D, Fournet JC, Papp E, McPherson EW, Zabel C, Vaksmann G, Morisot C, Keating B, Sleiman PM, Cleveland JA, Everman DB, Zackai E, Hakonarson H (2013) Mutations in PDGFRB cause autosomal-dominant infantile myofibromatosis. Am J Hum Genet 92(6):1001–1007. https://doi.org/10.1016/j.ajhg.2013.04.024

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Murray N, Hanna B, Graf N, Fu H, Mylene V, Campeau PM, Ronan A (2017) The spectrum of infantile myofibromatosis includes both non-penetrance and adult recurrence. Eur J Med Genet 60(7):353–358. https://doi.org/10.1016/j.ejmg.2017.02.005

    Article  PubMed  Google Scholar 

  60. Arts FA, Chand D, Pecquet C, Velghe AI, Constantinescu S, Hallberg B, Demoulin JB (2016) PDGFRB mutants found in patients with familial infantile myofibromatosis or overgrowth syndrome are oncogenic and sensitive to imatinib. Oncogene 35(25):3239–3248. https://doi.org/10.1038/onc.2015.383

    Article  CAS  PubMed  Google Scholar 

  61. Arts FA, Sciot R, Brichard B, Renard M, de Rocca SA, Dachy G, Noel LA, Velghe AI, Galant C, Debiec-Rychter M, Van Damme A, Vikkula M, Helaers R, Limaye N, Poirel HA, Demoulin JB (2017) PDGFRB gain-of-function mutations in sporadic infantile myofibromatosis. Hum Mol Genet 26(10):1801–1810. https://doi.org/10.1093/hmg/ddx081

    Article  CAS  PubMed  Google Scholar 

  62. Dachy G, de Krijger RR, Fraitag S, Theate I, Brichard B, Hoffman SB, Libbrecht L, Arts FA, Brouillard P, Vikkula M, Limaye N, Demoulin JB (2019) Association of PDGFRB mutations with pediatric myofibroma and myofibromatosis. JAMA Dermatol. https://doi.org/10.1001/jamadermatol.2019.0114

    Article  PubMed  PubMed Central  Google Scholar 

  63. Agaimy A, Bieg M, Michal M, Geddert H, Markl B, Seitz J, Moskalev EA, Schlesner M, Metzler M, Hartmann A, Wiemann S, Michal M, Mentzel T, Haller F (2017) Recurrent somatic PDGFRB mutations in sporadic infantile/solitary adult myofibromas but not in angioleiomyomas and myopericytomas. Am J Surg Pathol 41(2):195–203. https://doi.org/10.1097/pas.0000000000000752

    Article  PubMed  Google Scholar 

  64. Al Qawahmed R, Sawyer SL, Vassilyadi M, Qin W, Boycott KM, Michaud J (2019) Infantile myofibromatosis with intracranial extradural involvement and PDGFRB mutation: a case report and review of the literature. Pediatr Dev Pathol 22(3):258–264. https://doi.org/10.1177/1093526618787736

    Article  PubMed  Google Scholar 

  65. Weller JM, Keil VC, Gielen GH, Herrlinger U, Schafer N (2019) PDGRFB mutation-associated myofibromatosis: response to targeted therapy with imatinib. Am J Med Genet A 179(9):1895–1897. https://doi.org/10.1002/ajmg.a.61283

    Article  CAS  PubMed  Google Scholar 

  66. Takenouchi T, Yamaguchi Y, Tanikawa A, Kosaki R, Okano H, Kosaki K (2015) Novel overgrowth syndrome phenotype due to recurrent De Novo PDGFRB mutation. J Pediatr 166(2):483–486. https://doi.org/10.1016/j.jpeds.2014.10.015

    Article  PubMed  Google Scholar 

  67. Foster A, Chalot B, Antoniadi T, Schaefer E, Keelagher R, Ryan G, Thomas Q, Philippe C, Bruel AL, Sorlin A, Thauvin-Robinet C, Bardou M, Luu M, Quenardelle V, Wolff V, Woodley J, Vabres P, Lim D, Igbokwe R, Joseph A, Walker H, Jester A, Ellenbogen J, Johnson D, Rooke B, Moss C, Cole T, Faivre L (2020) Kosaki overgrowth syndrome: a novel pathogenic variant in PDGFRB and expansion of the phenotype including cerebrovascular complications. Clin Genet. https://doi.org/10.1111/cge.13752

    Article  PubMed  Google Scholar 

  68. Gawlinski P, Pelc M, Ciara E, Jhangiani S, Jurkiewicz E, Gambin T, Rozdzynska-Swiatkowska A, Dawidziuk M, Coban-Akdemir ZH, Guilbride DL, Muzny D, Lupski JR, Krajewska-Walasek M (2018) Phenotype expansion and development in Kosaki overgrowth syndrome. Clin Genet 93(4):919–924. https://doi.org/10.1111/cge.13192

    Article  CAS  PubMed  Google Scholar 

  69. Minatogawa M, Takenouchi T, Tsuyusaki Y, Iwasaki F, Uehara T, Kurosawa K, Kosaki K, Curry CJ (2017) Expansion of the phenotype of Kosaki overgrowth syndrome. Am J Med Genet A 173(9):2422–2427. https://doi.org/10.1002/ajmg.a.38310

    Article  CAS  PubMed  Google Scholar 

  70. Zarate YA, Boccuto L, Srikanth S, Pauly R, Ocal E, Balmakund T, Hinkle K, Stefans V, Schaefer GB, Collins RT 2nd (2019) Constitutive activation of the PI3K-AKT pathway and cardiovascular abnormalities in an individual with Kosaki overgrowth syndrome. Am J Med Genet A 179(6):1047–1052. https://doi.org/10.1002/ajmg.a.61145

    Article  CAS  PubMed  Google Scholar 

  71. Penttinen M, Niemi K-M, Vinkka-Puhakka H, Johansson R, Aula P (1997) New progeroid disorder. Am J Med Genet 69(2):182–187. https://doi.org/10.1002/(sici)1096-8628(19970317)69:2%3c182::Aid-ajmg13%3e3.0.Co;2-h

    Article  CAS  PubMed  Google Scholar 

  72. Johnston JJ, Sanchez-Contreras MY, Keppler-Noreuil KM, Sapp J, Crenshaw M, Finch NA, Cormier-Daire V, Rademakers R, Sybert VP, Biesecker LG (2015) A point mutation in PDGFRB causes autosomal-dominant penttinen syndrome. Am J Hum Genet 97(3):465–474. https://doi.org/10.1016/j.ajhg.2015.07.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. He C, Medley SC, Kim J, Sun C, Kwon HR, Sakashita H, Pincu Y, Yao L, Eppard D, Dai B, Berry WL, Griffin TM, Olson LE (2017) STAT1 modulates tissue wasting or overgrowth downstream from PDGFRβ. Genes Dev 31(16):1666–1678. https://doi.org/10.1101/gad.300384.117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Bredrup C, Stokowy T, McGaughran J, Lee S, Sapkota D, Cristea I, Xu L, Tveit KS, Hovding G, Steen VM, Rodahl E, Bruland O, Houge G (2019) A tyrosine kinase-activating variant Asn666Ser in PDGFRB causes a progeria-like condition in the severe end of Penttinen syndrome. Eur J Hum Genet 27(4):574–581. https://doi.org/10.1038/s41431-018-0323-z

    Article  CAS  PubMed  Google Scholar 

  75. Brasseur B, Chantrain CF, Godefroid N, Sluysmans T, Anslot C, Menten R, Clapuyt P, Dupont S, Vermylen C, Brichard B (2010) Development of renal and iliac aneurysms in a child with generalized infantile myofibromatosis. Pediatr Nephrol 25(5):983–986. https://doi.org/10.1007/s00467-009-1393-5

    Article  PubMed  Google Scholar 

  76. Wright C, Corbally MT, Hayes R, McDermott MB (2004) Multifocal infantile myofibromatosis and generalized fibromuscular dysplasia in a child: evidence for a common pathologic process? Pediatr Dev Pathol 7(4):385–390. https://doi.org/10.1007/s10024-003-0107-4

    Article  PubMed  Google Scholar 

  77. Karasozen Y, Osbun J, Parada C, Busald T, Tatman P, Gonzalez-Cuyar L, Hale C, Alcantara D, O’Driscoll M, Dobyns W, Murray M, Kim L, Byers P, Dorschner M, Ferreira M (2019) Somatic PDGFRB activating variants in fusiform cerebral aneurysms. Am J Human Genetics. https://doi.org/10.1016/j.ajhg.2019.03.014

    Article  Google Scholar 

  78. Zufferey F, Hadj-Rabia S, De Sandre-Giovannoli A, Dufier JL, Leheup B, Schweitze C, Bodemer C, Cormier-Daire V, Le Merrer M (2013) Acro-osteolysis, keloid like-lesions, distinctive facial features, and overgrowth: two newly recognized patients with premature aging syndrome, Penttinen type. Am J Med Genet A 161A(7):1786–1791. https://doi.org/10.1002/ajmg.a.35984

    Article  PubMed  Google Scholar 

  79. Guimier A, Gordon CT, Hully M, Blauwblomme T, Minard-Colin V, Bole-Feysot C, Nitschke P, Oufadem M, Boddaert N, Sarnacki S, Amiel J (2019) A novel de novo PDGFRB variant in a child with severe cerebral malformations, intracerebral calcifications, and infantile myofibromatosis. Am J Med Genet A 179(7):1304–1309. https://doi.org/10.1002/ajmg.a.61151

    Article  CAS  PubMed  Google Scholar 

  80. Pond D, Arts FA, Mendelsohn NJ, Demoulin JB, Scharer G, Messinger Y (2018) A patient with germ-line gain-of-function PDGFRB p.N666H mutation and marked clinical response to imatinib. Genet Med 20 (1):142–150. doi:https://doi.org/10.1038/gim.2017.104

  81. Wenger TL, Bly RA, Wu N, Albert CM, Park J, Shieh J, Chenbhanich J, Heike CL, Adam MP, Chang I, Sun A, Miller DE, Beck AE, Gupta D, Boos MD, Zackai EH, Everman D, Ganapathi S, Wilson M, Christodoulou J, Zarate YA, Curry C, Li D, Guimier A, Amiel J, Hakonarson H, Webster R, Bhoj EJ, Perkins JA, Dahl JP, Dobyns WB (2020) Activating variants in PDGFRB result in a spectrum of disorders responsive to imatinib monotherapy. Am J Med Genet A 182(7):1576–1591. https://doi.org/10.1002/ajmg.a.61615

    Article  CAS  PubMed  Google Scholar 

  82. Nicolas G, Pottier C, Charbonnier C, Guyant-Marechal L, Le Ber I, Pariente J, Labauge P, Ayrignac X, Defebvre L, Maltete D, Martinaud O, Lefaucheur R, Guillin O, Wallon D, Chaumette B, Rondepierre P, Derache N, Fromager G, Schaeffer S, Krystkowiak P, Verny C, Jurici S, Sauvee M, Verin M, Lebouvier T, Rouaud O, Thauvin-Robinet C, Rousseau S, Rovelet-Lecrux A, Frebourg T, Campion D, Hannequin D, French ISG (2013) Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification. Brain J Neurol 136(Pt 11):3395–3407. https://doi.org/10.1093/brain/awt255

    Article  Google Scholar 

  83. Nicolas G, Pottier C, Maltete D, Coutant S, Rovelet-Lecrux A, Legallic S, Rousseau S, Vaschalde Y, Guyant-Marechal L, Augustin J, Martinaud O, Defebvre L, Krystkowiak P, Pariente J, Clanet M, Labauge P, Ayrignac X, Lefaucheur R, Le Ber I, Frebourg T, Hannequin D, Campion D (2013) Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification. Neurology 80(2):181–187. https://doi.org/10.1212/WNL.0b013e31827ccf34

    Article  CAS  PubMed  Google Scholar 

  84. Sanchez-Contreras M, Baker MC, Finch NA, Nicholson A, Wojtas A, Wszolek ZK, Ross OA, Dickson DW, Rademakers R (2014) Genetic screening and functional characterization of PDGFRB mutations associated with basal ganglia calcification of unknown etiology. Hum Mutat 35(8):964–971. https://doi.org/10.1002/humu.22582

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Wang C, Yao XP, Chen HT, Lai JH, Guo XX, Su HZ, Dong EL, Zhang QJ, Wang N, Chen WJ (2017) Novel mutations of PDGFRB cause primary familial brain calcification in Chinese families. J Hum Genet. https://doi.org/10.1038/jhg.2017.25

    Article  PubMed  PubMed Central  Google Scholar 

  86. Betsholtz C, Keller A (2014) PDGF, pericytes and the pathogenesis of idiopathic basal ganglia calcification (IBGC). Brain Pathol 24(4):387–395. https://doi.org/10.1111/bpa.12158

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Manyam BV (2005) What is and what is not “Fahr’s disease.” Parkinsonism Relat Disord 11(2):73–80. https://doi.org/10.1016/j.parkreldis.2004.12.001

    Article  PubMed  Google Scholar 

  88. Arts FA, Velghe AI, Stevens M, Renauld JC, Essaghir A, Demoulin JB (2015) Idiopathic basal ganglia calcification-associated PDGFRB mutations impair the receptor signalling. J Cell Mol Med 19(1):239–248. https://doi.org/10.1111/jcmm.12443

    Article  CAS  PubMed  Google Scholar 

  89. Biancheri R, Severino M, Robbiano A, Iacomino M, Del Sette M, Minetti C, Cervasio M, Caro DBD, M, Striano P, Zara F, (2016) White matter involvement in a family with a novel PDGFB mutation. Neurol Genetics 2(3):e77. https://doi.org/10.1212/NXG.0000000000000077

    Article  Google Scholar 

  90. Keller A, Westenberger A, Sobrido MJ, Garcia-Murias M, Domingo A, Sears RL, Lemos RR, Ordonez-Ugalde A, Nicolas G, da Cunha JE, Rushing EJ, Hugelshofer M, Wurnig MC, Kaech A, Reimann R, Lohmann K, Dobricic V, Carracedo A, Petrovic I, Miyasaki JM, Abakumova I, Mae MA, Raschperger E, Zatz M, Zschiedrich K, Klepper J, Spiteri E, Prieto JM, Navas I, Preuss M, Dering C, Jankovic M, Paucar M, Svenningsson P, Saliminejad K, Khorshid HR, Novakovic I, Aguzzi A, Boss A, Le Ber I, Defer G, Hannequin D, Kostic VS, Campion D, Geschwind DH, Coppola G, Betsholtz C, Klein C, Oliveira JR (2013) Mutations in the gene encoding PDGF-B cause brain calcifications in humans and mice. Nat Genet 45:1077–1082. https://doi.org/10.1038/ng.2723

    Article  CAS  PubMed  Google Scholar 

  91. Keogh MJ, Pyle A, Daud D, Griffin H, Douroudis K, Eglon G, Miller J, Horvath R, Chinnery PF (2015) Clinical heterogeneity of primary familial brain calcification due to a novel mutation in PDGFB. Neurology 84(17):1818–1820. https://doi.org/10.1212/WNL.0000000000001517

    Article  PubMed  PubMed Central  Google Scholar 

  92. Nicolas G, Jacquin A, Thauvin-Robinet C, Rovelet-Lecrux A, Rouaud O, Pottier C, Aubriot-Lorton MH, Rousseau S, Wallon D, Duvillard C, Bejot Y, Frebourg T, Giroud M, Campion D, Hannequin D (2014) A de novo nonsense PDGFB mutation causing idiopathic basal ganglia calcification with laryngeal dystonia. Eur J Hum Genet. https://doi.org/10.1038/ejhg.2014.9

    Article  PubMed  PubMed Central  Google Scholar 

  93. Nicolas G, Rovelet-Lecrux A, Pottier C, Martinaud O, Wallon D, Vernier L, Landemore G, Chapon F, Prieto-Morin C, Tournier-Lasserve E, Frebourg T, Campion D, Hannequin D (2014) PDGFB partial deletion: a new, rare mechanism causing brain calcification with leukoencephalopathy. J Mol Neurosci 53(2):171–175. https://doi.org/10.1007/s12031-014-0265-z

    Article  CAS  PubMed  Google Scholar 

  94. Yao XP, Wang C, Su HZ, Guo XX, Lu YQ, Zhao M, Liu YB, Lai JH, Chen HT, Wang N, Chen WJ (2016) Mutation screening of PDGFB gene in Chinese population with primary familial brain calcification. Gene. https://doi.org/10.1016/j.gene.2016.10.037

    Article  PubMed  Google Scholar 

  95. Chen WJ, Yao XP, Zhang QJ, Ni W, He J, Li HF, Liu XY, Zhao GX, Murong SX, Wang N, Wu ZY (2013) Novel SLC20A2 mutations identified in southern Chinese patients with idiopathic basal ganglia calcification. Gene 529(1):159–162. https://doi.org/10.1016/j.gene.2013.07.071

    Article  CAS  PubMed  Google Scholar 

  96. David S, Ferreira J, Quenez O, Rovelet-Lecrux A, Richard AC, Verin M, Jurici S, Le Ber I, Boland A, Deleuze JF, Frebourg T, Mendes de Oliveira JR, Hannequin D, Campion D, Nicolas G (2016) Identification of partial SLC20A2 deletions in primary brain calcification using whole-exome sequencing. Eur J Hum Genet 24(11):1630–1634. https://doi.org/10.1038/ejhg.2016.50

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Gagliardi M, Morelli M, Annesi G, Nicoletti G, Perrotta P, Pustorino G, Iannello G, Tarantino P, Gambardella A, Quattrone A (2015) A new SLC20A2 mutation identified in southern Italy family with primary familial brain calcification. Gene 568(1):109–111. https://doi.org/10.1016/j.gene.2015.05.005

    Article  CAS  PubMed  Google Scholar 

  98. Gagliardi M, Morelli M, Iannello G, Colica C, Annesi G, Quattrone A (2017) A SLC20A2 mutation identified in an asymptomatic patient with brain calcification. J Neurol Sci 372:70–72. https://doi.org/10.1016/j.jns.2016.11.038

    Article  CAS  PubMed  Google Scholar 

  99. Hsu SC, Sears RL, Lemos RR, Quintans B, Huang A, Spiteri E, Nevarez L, Mamah C, Zatz M, Pierce KD, Fullerton JM, Adair JC, Berner JE, Bower M, Brodaty H, Carmona O, Dobricic V, Fogel BL, Garcia-Estevez D, Goldman J, Goudreau JL, Hopfer S, Jankovic M, Jauma S, Jen JC, Kirdlarp S, Klepper J, Kostic V, Lang AE, Linglart A, Maisenbacher MK, Manyam BV, Mazzoni P, Miedzybrodzka Z, Mitarnun W, Mitchell PB, Mueller J, Novakovic I, Paucar M, Paulson H, Simpson SA, Svenningsson P, Tuite P, Vitek J, Wetchaphanphesat S, Williams C, Yang M, Schofield PR, de Oliveira JR, Sobrido MJ, Geschwind DH, Coppola G (2013) Mutations in SLC20A2 are a major cause of familial idiopathic basal ganglia calcification. Neurogenetics 14(1):11–22. https://doi.org/10.1007/s10048-012-0349-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Lemos RR, Ramos EM, Legati A, Nicolas G, Jenkinson EM, Livingston JH, Crow YJ, Campion D, Coppola G, Oliveira JR (2015) Update and mutational analysis of SLC20A2: a major cause of primary familial brain calcification. Hum Mutat 36(5):489–495. https://doi.org/10.1002/humu.22778

    Article  CAS  PubMed  Google Scholar 

  101. Pasanen P, Makinen J, Myllykangas L, Guerreiro R, Bras J, Valori M, Viitanen M, Baumann M, Tienari PJ, Poyhonen M, Baumann P (2016) Primary familial brain calcification linked to deletion of 5’ noncoding region of SLC20A2. Acta Neurol Scand. https://doi.org/10.1111/ane.12697

    Article  PubMed  Google Scholar 

  102. Rubino E, Giorgio E, Godani M, Grosso E, Zibetti M, Lopiano L, Ferrero P, Duca S, Moretti L, Gallone S, Rainero I, Brusco A (2017) Three novel missense mutations in SLC20A2 associated with idiopathic basal ganglia calcification. J Neurol Sci 377:62–64. https://doi.org/10.1016/j.jns.2017.03.053

    Article  CAS  PubMed  Google Scholar 

  103. Wang C, Li Y, Shi L, Ren J, Patti M, Wang T, de Oliveira JR, Sobrido MJ, Quintans B, Baquero M, Cui X, Zhang XY, Wang L, Xu H, Wang J, Yao J, Dai X, Liu J, Zhang L, Ma H, Gao Y, Ma X, Feng S, Liu M, Wang QK, Forster IC, Zhang X, Liu JY (2012) Mutations in SLC20A2 link familial idiopathic basal ganglia calcification with phosphate homeostasis. Nat Genet 44(3):254–256. https://doi.org/10.1038/ng.1077

    Article  CAS  PubMed  Google Scholar 

  104. Anheim M, Lopez-Sanchez U, Giovannini D, Richard AC, Touhami J, N’Guyen L, Rudolf G, Thibault-Stoll A, Frebourg T, Hannequin D, Campion D, Battini JL, Sitbon M, Nicolas G (2016) XPR1 mutations are a rare cause of primary familial brain calcification. J Neurol 263(8):1559–1564. https://doi.org/10.1007/s00415-016-8166-4

    Article  CAS  PubMed  Google Scholar 

  105. Legati A, Giovannini D, Nicolas G, Lopez-Sanchez U, Quintans B, Oliveira JR, Sears RL, Ramos EM, Spiteri E, Sobrido MJ, Carracedo A, Castro-Fernandez C, Cubizolle S, Fogel BL, Goizet C, Jen JC, Kirdlarp S, Lang AE, Miedzybrodzka Z, Mitarnun W, Paucar M, Paulson H, Pariente J, Richard AC, Salins NS, Simpson SA, Striano P, Svenningsson P, Tison F, Unni VK, Vanakker O, Wessels MW, Wetchaphanphesat S, Yang M, Boller F, Campion D, Hannequin D, Sitbon M, Geschwind DH, Battini JL, Coppola G (2015) Mutations in XPR1 cause primary familial brain calcification associated with altered phosphate export. Nat Genet 47(6):579–581. https://doi.org/10.1038/ng.3289

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Jensen N, Schroder HD, Hejbol EK, Fuchtbauer EM, de Oliveira JR, Pedersen L (2013) Loss of function of Slc20a2 associated with familial idiopathic Basal Ganglia calcification in humans causes brain calcifications in mice. J Mol Neurosci 51(3):994–999. https://doi.org/10.1007/s12031-013-0085-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Demoulin JB, Ericsson J, Kallin A, Rorsman C, Ronnstrand L, Heldin CH (2004) Platelet-derived growth factor stimulates membrane lipid synthesis through activation of phosphatidylinositol 3-kinase and sterol regulatory element-binding proteins. J Biol Chem 279(34):35392–35402. https://doi.org/10.1074/jbc.M405924200

    Article  CAS  PubMed  Google Scholar 

  108. Kakita A, Suzuki A, Nishiwaki K, Ono Y, Kotake M, Ariyoshi Y, Miura Y, Ltoh M, Oiso Y (2004) Stimulation of Na-dependent phosphate transport by platelet-derived growth factor in rat aortic smooth muscle cells. Atherosclerosis 174(1):17–24. https://doi.org/10.1016/j.atherosclerosis.2003.12.039

    Article  CAS  PubMed  Google Scholar 

  109. Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature 468(7323):562–566. https://doi.org/10.1038/nature09513

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Zhao Z, Nelson AR, Betsholtz C, Zlokovic BV (2015) Establishment and dysfunction of the blood-brain barrier. Cell 163(5):1064–1078. https://doi.org/10.1016/j.cell.2015.10.067

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Vanlandewijck M, Lebouvier T, Andaloussi Mäe M, Nahar K, Hornemann S, Kenkel D, Cunha SI, Lennartsson J, Boss A, Heldin C-H, Keller A, Betsholtz C (2015) Functional characterization of germline mutations in PDGFB and PDGFRB in primary familial brain calcification. PLoS ONE 10(11):e0143407–e0143407. https://doi.org/10.1371/journal.pone.0143407

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Olson LE, Soriano P (2009) Increased PDGFRalpha activation disrupts connective tissue development and drives systemic fibrosis. Dev Cell 16(2):303–313. https://doi.org/10.1016/j.devcel.2008.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Suzuki S, Heldin CH, Heuchel RL (2007) Platelet-derived growth factor receptor-beta, carrying the activating mutation D849N, accelerates the establishment of B16 melanoma. BMC Cancer 7:224. https://doi.org/10.1186/1471-2407-7-224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Olson LE, Soriano P (2011) PDGFRbeta signaling regulates mural cell plasticity and inhibits fat development. Dev Cell 20(6):815–826. https://doi.org/10.1016/j.devcel.2011.04.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. He C, Medley SC, Hu T, Hinsdale ME, Lupu F, Virmani R, Olson LE (2015) PDGFRβ signalling regulates local inflammation and synergizes with hypercholesterolaemia to promote atherosclerosis. Nat Commun 6(1):7770. https://doi.org/10.1038/ncomms8770

    Article  CAS  PubMed  Google Scholar 

  116. Iwayama T, Steele C, Yao L, Dozmorov MG, Karamichos D, Wren JD, Olson LE (2015) PDGFRα signaling drives adipose tissue fibrosis by targeting progenitor cell plasticity. Genes Dev 29(11):1106–1119. https://doi.org/10.1101/gad.260554.115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Sun C, Sakashita H, Kim J, Tang Z, Upchurch GM, Yao L, Berry WL, Griffin TM, Olson LE (2020) Mosaic mutant analysis identifies PDGFRalpha/PDGFRbeta as negative regulators of adipogenesis. Cell Stem Cell 26 (5):707–721 e705. doi:https://doi.org/10.1016/j.stem.2020.03.004

  118. Liao X, Escobedo JA, Williams LT (1996) Viability of transgenic mice expressing a platelet derived growth factor (PDGF) antagonist in plasma. J Investig Med 44(4):139–143

    CAS  PubMed  Google Scholar 

  119. Floege J, Eitner F, Alpers CE (2008) A new look at platelet-derived growth factor in renal disease. J Am Soc Nephrol 19(1):12–23. https://doi.org/10.1681/asn.2007050532

    Article  CAS  PubMed  Google Scholar 

  120. Lassila M, Jandeleit-Dahm K, Seah KK, Smith CM, Calkin AC, Allen TJ, Cooper ME (2005) Imatinib attenuates diabetic nephropathy in apolipoprotein E-knockout mice. J Am Soc Nephrol 16(2):363–373. https://doi.org/10.1681/asn.2004050392

    Article  CAS  PubMed  Google Scholar 

  121. Wang S, Wilkes MC, Leof EB, Hirschberg R (2005) Imatinib mesylate blocks a non-Smad TGF-beta pathway and reduces renal fibrogenesis in vivo. Faseb j 19(1):1–11. https://doi.org/10.1096/fj.04-2370com

    Article  CAS  PubMed  Google Scholar 

  122. Zoja C, Corna D, Rottoli D, Zanchi C, Abbate M, Remuzzi G (2006) Imatinib ameliorates renal disease and survival in murine lupus autoimmune disease. Kidney Int 70(1):97–103. https://doi.org/10.1038/sj.ki.5001528

    Article  CAS  PubMed  Google Scholar 

  123. Lundby A, Franciosa G, Emdal KB, Refsgaard JC, Gnosa SP, Bekker-Jensen DB, Secher A, Maurya SR, Paul I, Mendez BL, Kelstrup CD, Francavilla C, Kveiborg M, Montoya G, Jensen LJ, Olsen JV (2019) Oncogenic mutations rewire signaling pathways by switching protein recruitment to phosphotyrosine sites. Cell 179(2):543-560.e526. https://doi.org/10.1016/j.cell.2019.09.008

    Article  CAS  PubMed  Google Scholar 

  124. Apperley JF, Gardembas M, Melo JV, Russell-Jones R, Bain BJ, Baxter EJ, Chase A, Chessells JM, Colombat M, Dearden CE, Dimitrijevic S, Mahon FX, Marin D, Nikolova Z, Olavarria E, Silberman S, Schultheis B, Cross NC, Goldman JM (2002) Response to imatinib mesylate in patients with chronic myeloproliferative diseases with rearrangements of the platelet-derived growth factor receptor beta. N Engl J Med 347(7):481–487. https://doi.org/10.1056/NEJMoa020150

    Article  CAS  PubMed  Google Scholar 

  125. Cheah CY, Burbury K, Apperley JF, Huguet F, Pitini V, Gardembas M, Ross DM, Forrest D, Genet P, Rousselot P, Patton N, Smith G, Dunbar CE, Ito S, Aguiar RCT, Odenike O, Gimelfarb A, Cross NCP, Seymour JF (2014) Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib. Blood 123(23):3574–3577. https://doi.org/10.1182/blood-2014-02-555607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Cools J, DeAngelo DJ, Gotlib J, Stover EH, Legare RD, Cortes J, Kutok J, Clark J, Galinsky I, Griffin JD, Cross NC, Tefferi A, Malone J, Alam R, Schrier SL, Schmid J, Rose M, Vandenberghe P, Verhoef G, Boogaerts M, Wlodarska I, Kantarjian H, Marynen P, Coutre SE, Stone R, Gilliland DG (2003) A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome. N Engl J Med 348(13):1201–1214. https://doi.org/10.1056/NEJMoa025217

    Article  CAS  PubMed  Google Scholar 

  127. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, Roberts PJ, Heinrich MC, Tuveson DA, Singer S, Janicek M, Fletcher JA, Silverman SG, Silberman SL, Capdeville R, Kiese B, Peng B, Dimitrijevic S, Druker BJ, Corless C, Fletcher CD, Joensuu H (2002) Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 347(7):472–480. https://doi.org/10.1056/NEJMoa020461

    Article  CAS  PubMed  Google Scholar 

  128. Heinrich MC, Griffith D, McKinley A, Patterson J, Presnell A, Ramachandran A, Debiec-Rychter M (2012) Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors. Clin Cancer Res 18(16):4375–4384. https://doi.org/10.1158/1078-0432.Ccr-12-0625

    Article  CAS  PubMed  Google Scholar 

  129. Evans EK, Gardino AK, Kim JL, Hodous BL, Shutes A, Davis A, Zhu XJ, Schmidt-Kittler O, Wilson D, Wilson K, DiPietro L, Zhang Y, Brooijmans N, LaBranche TP, Wozniak A, Gebreyohannes YK, Schöffski P, Heinrich MC, DeAngelo DJ, Miller S, Wolf B, Kohl N, Guzi T, Lydon N, Boral A, Lengauer C (2017) A precision therapy against cancers driven by <em>KIT/PDGFRA</em> mutations. Sci Transl Med 9 (414):eaao1690. doi:https://doi.org/10.1126/scitranslmed.aao1690

  130. Cheung E, Lobov IB, Cao J, Yancopaulos G, Romano C, Wiegand SJ (2015) Effects of combined inhibition of VEGF and PDGFRβ using aflibercept (VEGF Trap) and anti-PDGFRβ antibody on developing retinal angiogenesis in mice. Invest Ophthalmol Vis Sci 56(7):2314–2314

    Google Scholar 

  131. Loizos N, Xu Y, Huber J, Liu M, Lu D, Finnerty B, Rolser R, Malikzay A, Persaud A, Corcoran E, Deevi DS, Balderes P, Bassi R, Jimenez X, Joynes CJ, Mangalampalli VRM, Steiner P, Tonra JR, Wu Y, Pereira DS, Zhu Z, Ludwig DL, Hicklin DJ, Bohlen P, Witte L, Kussie P (2005) Targeting the platelet-derived growth factor receptor α with a neutralizing human monoclonal antibody inhibits the growth of tumor xenografts: Implications as a potential therapeutic target. Mol Cancer Ther 4(3):369–379. https://doi.org/10.1158/1535-7163.Mct-04-0114

    Article  CAS  PubMed  Google Scholar 

  132. Tap WD, Jones RL, Van Tine BA, Chmielowski B, Elias AD, Adkins D, Agulnik M, Cooney MM, Livingston MB, Pennock G, Hameed MR, Shah GD, Qin A, Shahir A, Cronier DM, Ilaria R Jr, Conti I, Cosaert J, Schwartz GK (2016) Olaratumab and doxorubicin versus doxorubicin alone for treatment of soft-tissue sarcoma: an open-label phase 1b and randomised phase 2 trial. Lancet 388(10043):488–497. https://doi.org/10.1016/s0140-6736(16)30587-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Cornillie J, Wozniak A, Van Renterghem B, Van Winkel N, Wellens J, Gebreyohannes YK, Debiec-Rychter M, Sciot R, Hompes D, Schöffski P (2019) Assessment of the platelet-derived growth factor receptor alpha antibody olaratumab in a panel of patient-derived soft tissue sarcoma xenografts. BMC Cancer 19(1):724. https://doi.org/10.1186/s12885-019-5872-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Heier JS, Wykoff CC, Waheed NK, Kitchens JW, Patel SS, Vitti R, Perlee L, Chu KW, Leal S, Asmus F, Son V, Schmelter T, Brown DM (2020) Intravitreal combined aflibercept + anti platelet-derived growth factor receptor b for neovascular age-related macular degeneration: results of the phase 2 CAPELLA trial. Ophthalmology 127(2):211–220. https://doi.org/10.1016/j.ophtha.2019.09.021

    Article  PubMed  Google Scholar 

  135. Camorani S, Esposito CL, Rienzo A, Catuogno S, Iaboni M, Condorelli G, de Franciscis V, Cerchia L (2014) Inhibition of receptor signaling and of glioblastoma-derived tumor growth by a novel PDGFRbeta aptamer. Mol Ther 22(4):828–841. https://doi.org/10.1038/mt.2013.300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Yoon S, Wu X, Armstrong B, Habib N, Rossi JJ (2019) An RNA aptamer targeting the receptor tyrosine kinase PDGFRalpha induces anti-tumor effects through STAT3 and p53 in glioblastoma. Mol Ther Nucleic Acids 14:131–141. https://doi.org/10.1016/j.omtn.2018.11.012

    Article  CAS  PubMed  Google Scholar 

  137. Romanelli A, Affinito A, Avitabile C, Catuogno S, Ceriotti P, Iaboni M, Modica J, Condorelli G, Catalucci D (2018) An anti-PDGFRβ aptamer for selective delivery of small therapeutic peptide to cardiac cells. PLoS ONE 13(3):e0193392. https://doi.org/10.1371/journal.pone.0193392

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors were supported by grants from the Foundation against Cancer and King-Baudouin Foundation (Belgium). E.G., F.A. and G.D. are recipients of fellowships from National Fund for Scientific Research (FNRS) (Belgium).

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  1. De Duve Institute, Université Catholique de Louvain, Avenue Hippocrate 75, Box B1.74.05, 1200, Brussels, Belgium

    Emilie Guérit, Florence Arts, Guillaume Dachy, Boutaina Boulouadnine & Jean-Baptiste Demoulin

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  1. Emilie Guérit
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  2. Florence Arts
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  3. Guillaume Dachy
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  4. Boutaina Boulouadnine
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  5. Jean-Baptiste Demoulin
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EG, FA, GD, BB and JBD wrote the manuscript. EG drew the figures.

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Correspondence to Jean-Baptiste Demoulin.

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Guérit, E., Arts, F., Dachy, G. et al. PDGF receptor mutations in human diseases. Cell. Mol. Life Sci. 78, 3867–3881 (2021). https://doi.org/10.1007/s00018-020-03753-y

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  • DOI: https://doi.org/10.1007/s00018-020-03753-y

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