MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression


Autoři: Tajana Tešan Tomić aff001;  Josefin Olausson aff001;  Anna Rehammar aff002;  Lily Deland aff001;  Andreas Muth aff003;  Katarina Ejeskär aff005;  Staffan Nilsson aff001;  Erik Kristiansson aff002;  Ola Nilsson Wassén aff006;  Frida Abel aff001
Působiště autorů: Department of Pathology and Genetics, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden aff001;  Department of Mathematical Sciences, Chalmers University of Technology and Biostatistics, School of Public Health and Community Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden aff002;  Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, Gothenburg, Sweden aff002;  Department of Surgery, Institute of Clinical Science, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden aff003;  Region Västra Götaland, Sahlgrenska University Hospital, Department of Surgery, Section of endocrine and sarcoma surgery, Gothenborg, Sweden aff004;  School of Health and Education, University of Skövde, Skövde, Sweden aff005;  Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden aff006
Vyšlo v časopise: MYO5B mutations in pheochromocytoma/paraganglioma promote cancer progression. PLoS Genet 16(6): e32767. doi:10.1371/journal.pgen.1008803
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008803

Souhrn

Identification of additional cancer-associated genes and secondary mutations driving the metastatic progression in pheochromocytoma and paraganglioma (PPGL) is important for subtyping, and may provide optimization of therapeutic regimens. We recently reported novel recurrent nonsynonymous mutations in the MYO5B gene in metastatic PPGL. Here, we explored the functional impact of these MYO5B mutations, and analyzed MYO5B expression in primary PPGL tumor cases in relation to mutation status. Immunohistochemistry and mRNA expression analysis in 30 PPGL tumors revealed an increased MYO5B expression in metastatic compared to non-metastatic cases. In addition, subcellular localization of MYO5B protein was altered from cytoplasmic to membranous in some metastatic tumors, and the strongest and most abnormal expression pattern was observed in a paraganglioma harboring a somatic MYO5B:p.G1611S mutation. In addition to five previously discovered MYO5B mutations, the present study of 30 PPGL (8 previous and 22 new samples) also revealed two, and hence recurrent, mutations in the gene paralog MYO5A. The three MYO5B missense mutations with the highest prediction scores (p.L587P, p.G1611S and p.R1641C) were selected and functionally validated using site directed mutagenesis and stable transfection into human neuroblastoma cells (SK-N-AS) and embryonic kidney cells (HEK293). In vitro analysis showed a significant increased proliferation rate in all three MYO5B mutated clones. The two somatically derived mutations, p.L587P and p.G1611S, were also found to increase the migration rate. Expression analysis of MYO5B mutants compared to wild type clones, demonstrated a significant enrichment of genes involved in migration, proliferation, cell adhesion, glucose metabolism, and cellular homeostasis. Our study validates the functional role of novel MYO5B mutations in proliferation and migration, and suggest the MYO5-pathway to be involved in the malignant progression in some PPGL tumors.

Klíčová slova:

Cytoplasm – Gene expression – Glucose metabolism – Membrane proteins – Metastatic tumors – Microarrays – Neurofibromatosis type 1 – Somatic mutation


Zdroje

1. Wangberg B, Muth A, Khorram-Manesh A, Jansson S, Nilsson O, Forssell-Aronsson E, et al. Malignant pheochromocytoma in a population-based study: survival and clinical results. Ann N Y Acad Sci. 2006;1073:512–6. doi: 10.1196/annals.1353.054 17102119

2. Kolackov K, Tupikowski K, Bednarek-Tupikowska G. Genetic aspects of pheochromocytoma. Adv Clin Exp Med. 2012;21(6):821–9. 23457139

3. Goldstein RE, O'Neill JA Jr., Holcomb GW 3rd, Morgan WM 3rd, Neblett WW 3rd, Oates JA, et al. Clinical experience over 48 years with pheochromocytoma. Ann Surg. 1999;229(6):755–64; discussion 64–6. doi: 10.1097/00000658-199906000-00001 10363888

4. Fishbein L, Leshchiner I, Walter V, Danilova L, Robertson AG, Johnson AR, et al. Comprehensive Molecular Characterization of Pheochromocytoma and Paraganglioma. Cancer Cell. 2017;31(2):181–93. doi: 10.1016/j.ccell.2017.01.001 28162975

5. Hescot S, Leboulleux S, Amar L, Vezzosi D, Borget I, Bournaud-Salinas C, et al. One-year progression-free survival of therapy-naive patients with malignant pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2013;98(10):4006–12. doi: 10.1210/jc.2013-1907 23884775

6. Favier J, Amar L, Gimenez-Roqueplo AP. Paraganglioma and phaeochromocytoma: from genetics to personalized medicine. Nat Rev Endocrinol. 2015;11(2):101–11. doi: 10.1038/nrendo.2014.188 25385035

7. Dahia PL. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nat Rev Cancer. 2014;14(2):108–19. doi: 10.1038/nrc3648 24442145

8. Muth A, Abel F, Jansson S, Nilsson O, Ahlman H, Wangberg B. Prevalence of germline mutations in patients with pheochromocytoma or abdominal paraganglioma and sporadic presentation: a population-based study in Western Sweden. World J Surg. 2012;36(6):1389–94. doi: 10.1007/s00268-012-1430-6 22270996

9. Buffet A, Morin A, Castro-Vega LJ, Habarou F, Lussey-Lepoutre C, Letouze E, et al. Germline Mutations in the Mitochondrial 2-Oxoglutarate/Malate Carrier SLC25A11 Gene Confer a Predisposition to Metastatic Paragangliomas. Cancer Res. 2018;78(8):1914–22. doi: 10.1158/0008-5472.CAN-17-2463 29431636

10. Cascon A, Comino-Mendez I, Curras-Freixes M, de Cubas AA, Contreras L, Richter S, et al. Whole-exome sequencing identifies MDH2 as a new familial paraganglioma gene. J Natl Cancer Inst. 2015;107(5).

11. Papathomas TG, Oudijk L, Zwarthoff EC, Post E, Duijkers FA, van Noesel MM, et al. Telomerase reverse transcriptase promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia. Endocr Relat Cancer. 2014;21(4):653–61. doi: 10.1530/ERC-13-0429 24951106

12. Remacha L, Curras-Freixes M, Torres-Ruiz R, Schiavi F, Torres-Perez R, Calsina B, et al. Gain-of-function mutations in DNMT3A in patients with paraganglioma. Genet Med. 2018;20(12):1644–51. doi: 10.1038/s41436-018-0003-y 29740169

13. Remacha L, Pirman D, Mahoney CE, Coloma J, Calsina B, Curras-Freixes M, et al. Recurrent Germline DLST Mutations in Individuals with Multiple Pheochromocytomas and Paragangliomas. Am J Hum Genet. 2019;104(5):1008–10. doi: 10.1016/j.ajhg.2019.04.010 31051110

14. Wilzen A, Rehammar A, Muth A, Nilsson O, Tesan Tomic T, Wangberg B, et al. Malignant pheochromocytomas/paragangliomas harbor mutations in transport and cell adhesion genes. Int J Cancer. 2016;138(9):2201–11. doi: 10.1002/ijc.29957 26650627

15. Yang C, Zhuang Z, Fliedner SM, Shankavaram U, Sun MG, Bullova P, et al. Germ-line PHD1 and PHD2 mutations detected in patients with pheochromocytoma/paraganglioma-polycythemia. J Mol Med (Berl). 2015;93(1):93–104. doi: 10.1007/s00109-014-1205-7 25263965

16. Jimenez C, Rohren E, Habra MA, Rich T, Jimenez P, Ayala-Ramirez M, et al. Current and future treatments for malignant pheochromocytoma and sympathetic paraganglioma. Curr Oncol Rep. 2013;15(4):356–71. doi: 10.1007/s11912-013-0320-x 23674235

17. Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, Landa I, Leandro-Garcia LJ, Leton R, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011;43(7):663–7. doi: 10.1038/ng.861 21685915

18. Fishbein L, Khare S, Wubbenhorst B, DeSloover D, D'Andrea K, Merrill S, et al. Whole-exome sequencing identifies somatic ATRX mutations in pheochromocytomas and paragangliomas. Nature communications. 2015;6:6140. doi: 10.1038/ncomms7140 25608029

19. Thompson LD. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol. 2002;26(5):551–66. doi: 10.1097/00000478-200205000-00002 11979086

20. Ouderkirk JL, Krendel M. Non-muscle myosins in tumor progression, cancer cell invasion, and metastasis. Cytoskeleton (Hoboken). 2014;71(8):447–63.

21. Lapierre LA, Kumar R, Hales CM, Navarre J, Bhartur SG, Burnette JO, et al. Myosin vb is associated with plasma membrane recycling systems. Mol Biol Cell. 2001;12(6):1843–57. doi: 10.1091/mbc.12.6.1843 11408590

22. Schafer JC, Baetz NW, Lapierre LA, McRae RE, Roland JT, Goldenring JR. Rab11-FIP2 interaction with MYO5B regulates movement of Rab11a-containing recycling vesicles. Traffic. 2014;15(3):292–308. doi: 10.1111/tra.12146 24372966

23. Roland JT, Bryant DM, Datta A, Itzen A, Mostov KE, Goldenring JR. Rab GTPase-Myo5B complexes control membrane recycling and epithelial polarization. Proc Natl Acad Sci U S A. 2011;108(7):2789–94. doi: 10.1073/pnas.1010754108 21282656

24. Kravtsov D, Mashukova A, Forteza R, Rodriguez MM, Ameen NA, Salas PJ. Myosin 5b loss of function leads to defects in polarized signaling: implication for microvillus inclusion disease pathogenesis and treatment. Am J Physiol Gastrointest Liver Physiol. 2014;307(10):G992–G1001. doi: 10.1152/ajpgi.00180.2014 25258405

25. Muller T, Hess MW, Schiefermeier N, Pfaller K, Ebner HL, Heinz-Erian P, et al. MYO5B mutations cause microvillus inclusion disease and disrupt epithelial cell polarity. Nat Genet. 2008;40(10):1163–5. doi: 10.1038/ng.225 18724368

26. van der Velde KJ, Dhekne HS, Swertz MA, Sirigu S, Ropars V, Vinke PC, et al. An overview and online registry of microvillus inclusion disease patients and their MYO5B mutations. Hum Mutat. 2013;34(12):1597–605. doi: 10.1002/humu.22440 24014347

27. Thoeni CE, Vogel GF, Tancevski I, Geley S, Lechner S, Pfaller K, et al. Microvillus inclusion disease: loss of Myosin vb disrupts intracellular traffic and cell polarity. Traffic. 2014;15(1):22–42. doi: 10.1111/tra.12131 24138727

28. Li YR, Yang WX. Myosin superfamily: The multi-functional and irreplaceable factors in spermatogenesis and testicular tumors. Gene. 2016;576(1 Pt 2):195–207.

29. Lan L, Han H, Zuo H, Chen Z, Du Y, Zhao W, et al. Upregulation of myosin Va by Snail is involved in cancer cell migration and metastasis. Int J Cancer. 2010;126(1):53–64. doi: 10.1002/ijc.24641 19521958

30. Dong W, Chen X, Chen P, Yue D, Zhu L, Fan Q. Inactivation of MYO5B promotes invasion and motility in gastric cancer cells. Digestive diseases and sciences. 2012;57(5):1247–52. doi: 10.1007/s10620-011-1989-z 22134786

31. Dong W, Wang L, Shen R. MYO5B is epigenetically silenced and associated with MET signaling in human gastric cancer. Digestive diseases and sciences. 2013;58(7):2038–45. doi: 10.1007/s10620-013-2600-6 23456500

32. Letellier E, Schmitz M, Ginolhac A, Rodriguez F, Ullmann P, Qureshi-Baig K, et al. Loss of Myosin Vb in colorectal cancer is a strong prognostic factor for disease recurrence. Br J Cancer. 2017;117(11):1689–701. doi: 10.1038/bjc.2017.352 29024942

33. Knowles BC, Roland JT, Krishnan M, Tyska MJ, Lapierre LA, Dickman PS, et al. Myosin Vb uncoupling from RAB8A and RAB11A elicits microvillus inclusion disease. J Clin Invest. 2014;124(7):2947–62. doi: 10.1172/JCI71651 24892806

34. Rief M, Rock RS, Mehta AD, Mooseker MS, Cheney RE, Spudich JA. Myosin-V stepping kinetics: a molecular model for processivity. Proc Natl Acad Sci U S A. 2000;97(17):9482–6. doi: 10.1073/pnas.97.17.9482 10944217

35. Klein M, Vignaud JM, Hennequin V, Toussaint B, Bresler L, Plenat F, et al. Increased expression of the vascular endothelial growth factor is a pejorative prognosis marker in papillary thyroid carcinoma. J Clin Endocrinol Metab. 2001;86(2):656–8. doi: 10.1210/jcem.86.2.7226 11158026

36. Dahia PL, Ross KN, Wright ME, Hayashida CY, Santagata S, Barontini M, et al. A HIF1alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 2005;1(1):72–80. doi: 10.1371/journal.pgen.0010008 16103922

37. Evenepoel L, Papathomas TG, Krol N, Korpershoek E, de Krijger RR, Persu A, et al. Toward an improved definition of the genetic and tumor spectrum associated with SDH germ-line mutations. Genet Med. 2015;17(8):610–20. doi: 10.1038/gim.2014.162 25394176

38. Eden E, Navon R, Steinfeld I, Lipson D, Yakhini Z. GOrilla: a tool for discovery and visualization of enriched GO terms in ranked gene lists. BMC Bioinformatics. 2009;10:48. doi: 10.1186/1471-2105-10-48 19192299

39. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50. doi: 10.1073/pnas.0506580102 16199517

40. Varemo L, Nielsen J, Nookaew I. Enriching the gene set analysis of genome-wide data by incorporating directionality of gene expression and combining statistical hypotheses and methods. Nucleic Acids Res. 2013;41(8):4378–91. doi: 10.1093/nar/gkt111 23444143

41. Astuti D, Morris M, Krona C, Abel F, Gentle D, Martinsson T, et al. Investigation of the role of SDHB inactivation in sporadic phaeochromocytoma and neuroblastoma. Br J Cancer. 2004;91(10):1835–41. doi: 10.1038/sj.bjc.6602202 15505628

42. El-Badry OM, Romanus JA, Helman LJ, Cooper MJ, Rechler MM, Israel MA. Autonomous growth of a human neuroblastoma cell line is mediated by insulin-like growth factor II. J Clin Invest. 1989;84(3):829–39. doi: 10.1172/JCI114243 2547840

43. Rapizzi E, Ercolino T, Fucci R, Zampetti B, Felici R, Guasti D, et al. Succinate dehydrogenase subunit B mutations modify human neuroblastoma cell metabolism and proliferation. Horm Cancer. 2014;5(3):174–84. doi: 10.1007/s12672-014-0172-3 24595825

44. Rapizzi E, Fucci R, Giannoni E, Canu L, Richter S, Cirri P, et al. Role of microenvironment on neuroblastoma SK-N-AS SDHB-silenced cell metabolism and function. Endocr Relat Cancer. 2015;22(3):409–17. doi: 10.1530/ERC-14-0479 25808177

45. Royer C, Lu X. Epithelial cell polarity: a major gatekeeper against cancer? Cell Death Differ. 2011;18(9):1470–7. doi: 10.1038/cdd.2011.60 21617693

46. Izidoro-Toledo TC, Borges AC, Araujo DD, Mazzi DP, Nascimento Junior FO, Sousa JF, et al. A myosin-Va tail fragment sequesters dynein light chains leading to apoptosis in melanoma cells. Cell Death Dis. 2013;4:e547. doi: 10.1038/cddis.2013.45 23519116

47. Li YR, Yang WX. Myosins as fundamental components during tumorigenesis: diverse and indispensable. Oncotarget. 2016;7(29):46785–812. doi: 10.18632/oncotarget.8800 27121062

48. Daniels TR, Bernabeu E, Rodriguez JA, Patel S, Kozman M, Chiappetta DA, et al. The transferrin receptor and the targeted delivery of therapeutic agents against cancer. Biochim Biophys Acta. 2012;1820(3):291–317. doi: 10.1016/j.bbagen.2011.07.016 21851850

49. Olsson M, Beck S, Kogner P, Martinsson T, Caren H. Genome-wide methylation profiling identifies novel methylated genes in neuroblastoma tumors. Epigenetics. 2016;11(1):74–84. doi: 10.1080/15592294.2016.1138195 26786290

50. Kim J, Kim WH, Byeon SJ, Lee BL, Kim MA. Epigenetic Downregulation and Growth Inhibition of IGFBP7 in Gastric Cancer. Asian Pac J Cancer Prev. 2018;19(3):667–75. doi: 10.22034/APJCP.2018.19.3.667 29580038

51. Akiel M, Guo C, Li X, Rajasekaran D, Mendoza RG, Robertson CL, et al. IGFBP7 Deletion Promotes Hepatocellular Carcinoma. Cancer Res. 2017;77(15):4014–25. doi: 10.1158/0008-5472.CAN-16-2885 28619711

52. Chuanyu S, Yuqing Z, Chong X, Guowei X, Xiaojun Z. Periostin promotes migration and invasion of renal cell carcinoma through the integrin/focal adhesion kinase/c-Jun N-terminal kinase pathway. Tumour Biol. 2017;39(4):1010428317694549. doi: 10.1177/1010428317694549 28381189

53. Gonzalez-Gonzalez L, Alonso J. Periostin: A Matricellular Protein With Multiple Functions in Cancer Development and Progression. Front Oncol. 2018;8:225. doi: 10.3389/fonc.2018.00225 29946533

54. Cai T, Chen X, Wang R, Xu H, You Y, Zhang T, et al. Expression of insulinoma-associated 2 (INSM2) in pancreatic islet cells is regulated by the transcription factors Ngn3 and NeuroD1. Endocrinology. 2011;152(5):1961–9. doi: 10.1210/en.2010-1065 21343251

55. Wang L, Sun ZS, Xiang B, Wei CJ, Wang Y, Sun K, et al. Targeted deletion of Insm2 in mice result in reduced insulin secretion and glucose intolerance. J Transl Med. 2018;16(1):297. doi: 10.1186/s12967-018-1665-6 30359270

56. Jyotsna VP, Malik E, Birla S, Sharma A. Novel MEN 1 gene findings in rare sporadic insulinoma—a case control study. BMC Endocr Disord. 2015;15:44. doi: 10.1186/s12902-015-0041-2 26307114

57. Yagi T, Kubota E, Koyama H, Tanaka T, Kataoka H, Imaeda K, et al. Glucagon promotes colon cancer cell growth via regulating AMPK and MAPK pathways. Oncotarget. 2018;9(12):10650–64. doi: 10.18632/oncotarget.24367 29535833

58. Sosnicki S, Kapral M, Weglarz L. Molecular targets of metformin antitumor action. Pharmacol Rep. 2016;68(5):918–25. doi: 10.1016/j.pharep.2016.04.021 27362768

59. Daugan M, Dufay Wojcicki A, d'Hayer B, Boudy V. Metformin: An anti-diabetic drug to fight cancer. Pharmacol Res. 2016;113(Pt A):675–85. doi: 10.1016/j.phrs.2016.10.006 27720766

60. Li M, Jiang X, Su T, Jiang L, Zhou W, Wang W. Metformin Suppresses Proliferation and Viability of Rat Pheochromocytoma Cells. Med Sci Monit. 2017;23:3253–60. doi: 10.12659/msm.903348 28675758

61. Lopez-Jimenez E, Gomez-Lopez G, Leandro-Garcia LJ, Munoz I, Schiavi F, Montero-Conde C, et al. Research resource: Transcriptional profiling reveals different pseudohypoxic signatures in SDHB and VHL-related pheochromocytomas. Mol Endocrinol. 2010;24(12):2382–91. doi: 10.1210/me.2010-0256 20980436

62. Jochmanova I, Pacak K. Pheochromocytoma: The First Metabolic Endocrine Cancer. Clin Cancer Res. 2016;22(20):5001–11. doi: 10.1158/1078-0432.CCR-16-0606 27742786

63. Favier J, Briere JJ, Burnichon N, Riviere J, Vescovo L, Benit P, et al. The Warburg effect is genetically determined in inherited pheochromocytomas. PLoS One. 2009;4(9):e7094. doi: 10.1371/journal.pone.0007094 19763184

64. van Berkel A, Rao JU, Kusters B, Demir T, Visser E, Mensenkamp AR, et al. Correlation between in vivo 18F-FDG PET and immunohistochemical markers of glucose uptake and metabolism in pheochromocytoma and paraganglioma. J Nucl Med. 2014;55(8):1253–9. doi: 10.2967/jnumed.114.137034 24925884

65. van Lennep JR, Romijn JA, Harinck HI. Multi-organ failure after a glucagon test. Lancet. 2007;369(9563):798. doi: 10.1016/S0140-6736(07)60365-1 17336657

66. Hosseinnezhad A, Black RM, Aeddula NR, Adhikari D, Trivedi N. Glucagon-induced pheochromocytoma crisis. Endocr Pract. 2011;17(3):e51–4. doi: 10.4158/EP10388.CR 21324811

67. Legler A, Kim RK, Chawla N. Glucagon-induced hypertensive emergency: a case report. J Clin Anesth. 2016;35:493–6. doi: 10.1016/j.jclinane.2016.08.033 27871582

68. Lenders JW, Pacak K, Huynh TT, Sharabi Y, Mannelli M, Bratslavsky G, et al. Low sensitivity of glucagon provocative testing for diagnosis of pheochromocytoma. J Clin Endocrinol Metab. 2010;95(1):238–45. doi: 10.1210/jc.2009-1850 19897672

69. Lussey-Lepoutre C, Hollinshead KE, Ludwig C, Menara M, Morin A, Castro-Vega LJ, et al. Loss of succinate dehydrogenase activity results in dependency on pyruvate carboxylation for cellular anabolism. Nature communications. 2015;6:8784. doi: 10.1038/ncomms9784 26522426

70. Castro-Vega LJ, Letouze E, Burnichon N, Buffet A, Disderot PH, Khalifa E, et al. Multi-omics analysis defines core genomic alterations in pheochromocytomas and paragangliomas. Nature communications. 2015;6:6044. doi: 10.1038/ncomms7044 25625332

71. Dwight T, Na U, Kim E, Zhu Y, Richardson AL, Robinson BG, et al. Analysis of SDHAF3 in familial and sporadic pheochromocytoma and paraganglioma. BMC Cancer. 2017;17(1):497. doi: 10.1186/s12885-017-3486-z 28738844

72. Flynn A, Benn D, Clifton-Bligh R, Robinson B, Trainer AH, James P, et al. The genomic landscape of phaeochromocytoma. J Pathol. 2015;236(1):78–89. doi: 10.1002/path.4503 25545346

73. Juhlin CC, Stenman A, Haglund F, Clark VE, Brown TC, Baranoski J, et al. Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene. Genes Chromosomes Cancer. 2015;54(9):542–54. doi: 10.1002/gcc.22267 26032282

74. Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9(7):671–5. doi: 10.1038/nmeth.2089 22930834

75. Schindelin J, Arganda-Carreras I, Frise E, Kaynig V, Longair M, Pietzsch T, et al. Fiji: an open-source platform for biological-image analysis. Nat Methods. 2012;9(7):676–82. doi: 10.1038/nmeth.2019 22743772

76. Qiu YL, Gong JY, Feng JY, Wang RX, Han J, Liu T, et al. Defects in myosin VB are associated with a spectrum of previously undiagnosed low gamma-glutamyltransferase cholestasis. Hepatology. 2017;65(5):1655–69. doi: 10.1002/hep.29020 28027573

77. Yeh IT, Lenci RE, Qin Y, Buddavarapu K, Ligon AH, Leteurtre E, et al. A germline mutation of the KIF1B beta gene on 1p36 in a family with neural and nonneural tumors. Hum Genet. 2008;124(3):279–85. doi: 10.1007/s00439-008-0553-1 18726616

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