A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease


Autoři: Tanja Mederer aff001;  Stefanie Schmitteckert aff001;  Julia Volz aff001;  Cristina Martínez aff001;  Ralph Röth aff001;  Thomas Thumberger aff004;  Volker Eckstein aff005;  Jutta Scheuerer aff006;  Cornelia Thöni aff006;  Felix Lasitschka aff006;  Leonie Carstensen aff007;  Patrick Günther aff007;  Stefan Holland-Cunz aff008;  Robert Hofstra aff009;  Erwin Brosens aff009;  Jill A. Rosenfeld aff010;  Christian P. Schaaf aff010;  Duco Schriemer aff013;  Isabella Ceccherini aff014;  Marta Rusmini aff014;  Joseph Tilghman aff015;  Berta Luzón-Toro aff016;  Ana Torroglosa aff016;  Salud Borrego aff016;  Clara Sze-man Tang aff018;  Mercè Garcia-Barceló aff018;  Paul Tam aff018;  Nagarajan Paramasivam aff019;  Melanie Bewerunge-Hudler aff020;  Carolina De La Torre aff021;  Norbert Gretz aff021;  Gudrun A. Rappold aff001;  Philipp Romero aff007;  Beate Niesler aff001
Působiště autorů: Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany aff001;  Lleida Institute for Biomedical Research Dr. Pifarré Foundation (IRBLleida), Lleida, Spain aff002;  nCounter Core Facility, Department of Human Molecular Genetics, Heidelberg University Hospital, Heidelberg, Germany aff003;  Centre for Organismal Studies, Heidelberg University, Heidelberg, Germany aff004;  FACS Core Facility, Campus Heidelberg, Germany aff005;  Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany aff006;  Pediatric Surgery Division, Heidelberg University Hospital, Heidelberg, Germany aff007;  Pediatric Surgery, University Children's Hospital, Basel, Switzerland aff008;  Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands aff009;  Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America aff010;  Baylor Genetics Laboratories, Houston, Texas, United States of America aff011;  Institute of Human Genetics, Heidelberg University Hospital, Heidelberg, Germany aff012;  Department of Neuroscience, University Medical Center, Groningen, The Netherlands aff013;  UOSD Genetica e Genomica delle Malattie Rare, IRCCS, Instituto Giannina Gaslini, Genova, Italy aff014;  Center for Human Genetics and Genomics, New York University School of Medicine, United States of America aff015;  Department of Maternofetal Medicine, Genetics and Reproduction, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville, Seville, Spain aff016;  Centre for Biomedical Network Research on Rare Diseases (CIBERER), Seville, Spain aff017;  Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China aff018;  Division of Theoretical Bioinformatics, German Cancer Research Center, Heidelberg, Germany aff019;  Genomics and Proteomic Core Facility, German Cancer Research Center, Heidelberg, Germany aff020;  Center of Medical Research, Medical Faculty Mannheim, Mannheim, Germany aff021;  Interdisciplinary Center for Neurosciences, University of Heidelberg, Heidelberg, Germany aff022
Vyšlo v časopise: A complementary study approach unravels novel players in the pathoetiology of Hirschsprung disease. PLoS Genet 16(11): e32767. doi:10.1371/journal.pgen.1009106
Kategorie: Research Article
doi: 10.1371/journal.pgen.1009106

Souhrn

Hirschsprung disease (HSCR, OMIM 142623) involves congenital intestinal obstruction caused by dysfunction of neural crest cells and their progeny during enteric nervous system (ENS) development. HSCR is a multifactorial disorder; pathogenetic variants accounting for disease phenotype are identified only in a minority of cases, and the identification of novel disease-relevant genes remains challenging. In order to identify and to validate a potential disease-causing relevance of novel HSCR candidate genes, we established a complementary study approach, combining whole exome sequencing (WES) with transcriptome analysis of murine embryonic ENS-related tissues, literature and database searches, in silico network analyses, and functional readouts using candidate gene-specific genome-edited cell clones. WES datasets of two patients with HSCR and their non-affected parents were analysed, and four novel HSCR candidate genes could be identified: ATP7A, SREBF1, ABCD1 and PIAS2. Further rare variants in these genes were identified in additional HSCR patients, suggesting disease relevance. Transcriptomics revealed that these genes are expressed in embryonic and fetal gastrointestinal tissues. Knockout of these genes in neuronal cells demonstrated impaired cell differentiation, proliferation and/or survival. Our approach identified and validated candidate HSCR genes and provided further insight into the underlying pathomechanisms of HSCR.

Klíčová slova:

Cell differentiation – Cloning – Computer-aided drug design – Gene cloning – Gene expression – Hirschsprung disease – Human genetics – Neuronal differentiation


Zdroje

1. Amiel J, Sproat-Emison E, Garcia-Barcelo M, Lantieri F, Burzynski G, Borrego S, et al. Hirschsprung disease, associated syndromes and genetics: a review. J Med Genet. 2008;45(1):1–14. doi: 10.1136/jmg.2007.053959 17965226

2. Parisi MA. Hirschsprung Disease Overview. GeneReviews [Internet]. 2002 Jul 12 [Updated 2015 Oct 1].

3. Goldstein AM, Hofstra RM, Burns AJ. Building a brain in the gut: development of the enteric nervous system. Clin Genet. 2013;83(4):307–16. doi: 10.1111/cge.12054 23167617

4. Sasselli V, Pachnis V, Burns AJ. The enteric nervous system. Developmental biology. 2012;366(1):64–73. doi: 10.1016/j.ydbio.2012.01.012 22290331

5. Rao M, Gershon MD. Enteric nervous system development: what could possibly go wrong? Nature reviews Neuroscience. 2018;19(9):552–65. doi: 10.1038/s41583-018-0041-0 30046054

6. Furness JB. The enteric nervous system: Blackwell Publishing; 2006.

7. Heanue TA, Pachnis V. Enteric nervous system development and Hirschsprung's disease: advances in genetic and stem cell studies. Nature reviews Neuroscience. 2007;8(6):466–79. doi: 10.1038/nrn2137 17514199

8. Tilghman JM, Ling AY, Turner TN, Sosa MX, Krumm N, Chatterjee S, et al. Molecular Genetic Anatomy and Risk Profile of Hirschsprung's Disease. N Engl J Med. 2019;380(15):1421–32. doi: 10.1056/NEJMoa1706594 30970187

9. Luzón-Toro B, Villalba-Benito L, Torroglosa A, Fernández RM, Antiñolo G, Borrego S. What is new about the genetic background of Hirschsprung disease? Clinical Genetics. 2019;0(ja).

10. Luzón-Toro B, Gui H, Ruiz-Ferrer M, Sze-Man Tang C, Fernandez RM, Sham PC, et al. Exome sequencing reveals a high genetic heterogeneity on familial Hirschsprung disease. Scientific reports. 2015;5:16473. doi: 10.1038/srep16473 26559152

11. Bahrami A, Joodi M, Moetamani-Ahmadi M, Maftouh M, Hassanian SM, Ferns GA, et al. Genetic Background of Hirschsprung Disease: A Bridge Between Basic Science and Clinical Application. J Cell Biochem. 2017.

12. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nature genetics. 2014;46(3):310–5. doi: 10.1038/ng.2892 24487276

13. McCann CJ, Alves MM, Brosens E, Natarajan D, Perin S, Chapman C, et al. Neuronal Development and Onset of Electrical Activity in the Human Enteric Nervous System. Gastroenterology. 2019;156(5):1483–95.e6. doi: 10.1053/j.gastro.2018.12.020 30610864

14. Furness JB, Stebbing MJ. The first brain: Species comparisons and evolutionary implications for the enteric and central nervous systems. Neurogastroenterology and motility: the official journal of the European Gastrointestinal Motility Society. 2018;30(2).

15. Mayer EA, Tillisch K. The brain-gut axis in abdominal pain syndromes. Annual review of medicine. 2011;62:381–96. doi: 10.1146/annurev-med-012309-103958 21090962

16. Gui H, Schriemer D, Cheng WW, Chauhan RK, Antinolo G, Berrios C, et al. Whole exome sequencing coupled with unbiased functional analysis reveals new Hirschsprung disease genes. Genome biology. 2017;18(1):48. doi: 10.1186/s13059-017-1174-6 28274275

17. Rao M, Gershon MD. The bowel and beyond: the enteric nervous system in neurological disorders. Nature reviews Gastroenterology & hepatology. 2016;13(9):517–28.

18. Tang CS, Gui H, Kapoor A, Kim JH, Luzon-Toro B, Pelet A, et al. Trans-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease. Human molecular genetics. 2016;25(23):5265–75. doi: 10.1093/hmg/ddw333 27702942

19. Bernier R, Golzio C, Xiong B, Stessman HA, Coe BP, Penn O, et al. Disruptive CHD8 mutations define a subtype of autism early in development. Cell. 2014;158(2):263–76. doi: 10.1016/j.cell.2014.06.017 24998929

20. Hosie S, Ellis M, Swaminathan M, Ramalhosa F, Seger GO, Balasuriya GK, et al. Gastrointestinal dysfunction in patients and mice expressing the autism-associated R451C mutation in neuroligin-3. Autism Res. 2019;12(7):1043–56. doi: 10.1002/aur.2127 31119867

21. Li Y, Liu H, Dong Y. Significance of neurexin and neuroligin polymorphisms in regulating risk of Hirschsprung's disease. J Investig Med. 2018;66(5):1–8.

22. Niesler BR G.A. Emerging evidence for gene mutations driving both brain and gut dysfunction in autism spectrum disorder. Molecular Psychiatry. 2020.

23. Kaler SG. ATP7A-related copper transport diseases-emerging concepts and future trends. Nature reviews Neurology. 2011;7(1):15–29. doi: 10.1038/nrneurol.2010.180 21221114

24. Kemp S, Theodoulou FL, Wanders RJ. Mammalian peroxisomal ABC transporters: from endogenous substrates to pathology and clinical significance. Br J Pharmacol. 2011;164(7):1753–66. doi: 10.1111/j.1476-5381.2011.01435.x 21488864

25. Eberle D, Hegarty B, Bossard P, Ferre P, Foufelle F. SREBP transcription factors: master regulators of lipid homeostasis. Biochimie. 2004;86(11):839–48. doi: 10.1016/j.biochi.2004.09.018 15589694

26. Kotaja N, Karvonen U, Janne OA, Palvimo JJ. PIAS proteins modulate transcription factors by functioning as SUMO-1 ligases. Molecular and cellular biology. 2002;22(14):5222–34. doi: 10.1128/mcb.22.14.5222-5234.2002 12077349

27. Rott R, Szargel R, Shani V, Hamza H, Savyon M, Abd Elghani F, et al. SUMOylation and ubiquitination reciprocally regulate α-synuclein degradation and pathological aggregation. Proceedings of the National Academy of Sciences of the United States of America. 2017;114(50):13176–81. doi: 10.1073/pnas.1704351114 29180403

28. Spell C, Kolsch H, Lutjohann D, Kerksiek A, Hentschel F, Damian M, et al. SREBP-1a polymorphism influences the risk of Alzheimer's disease in carriers of the ApoE4 allele. Dement Geriatr Cogn Disord. 2004;18(3–4):245–9. doi: 10.1159/000080023 15286454

29. Jeong S, Liang G, Sharma S, Lin JC, Choi SH, Han H, et al. Selective anchoring of DNA methyltransferases 3A and 3B to nucleosomes containing methylated DNA. Molecular and cellular biology. 2009;29(19):5366–76. doi: 10.1128/MCB.00484-09 19620278

30. Wang W, Chen Y, Wang S, Hu N, Cao Z, Wang W, et al. PIASxalpha ligase enhances SUMO1 modification of PTEN protein as a SUMO E3 ligase. The Journal of biological chemistry. 2014;289(6):3217–30. doi: 10.1074/jbc.M113.508515 24344134

31. Lee JH, Lee GY, Jang H, Choe SS, Koo SH, Kim JB. Ring finger protein20 regulates hepatic lipid metabolism through protein kinase A-dependent sterol regulatory element binding protein1c degradation. Hepatology. 2014;60(3):844–57. doi: 10.1002/hep.27011 24425205

32. Wallace AS, Anderson RB. Genetic interactions and modifier genes in Hirschsprung's disease. World journal of gastroenterology. 2011;17(45):4937–44. doi: 10.3748/wjg.v17.i45.4937 22174542

33. Telianidis J, Hung YH, Materia S, Fontaine SL. Role of the P-Type ATPases, ATP7A and ATP7B in brain copper homeostasis. Frontiers in aging neuroscience. 2013;5:44. doi: 10.3389/fnagi.2013.00044 23986700

34. Wilentz RE, Witters LA, Pizer ES. Lipogenic enzymes fatty acid synthase and acetyl-coenzyme A carboxylase are coexpressed with sterol regulatory element binding protein and Ki-67 in fetal tissues. Pediatr Dev Pathol. 2000;3(6):525–31. doi: 10.1007/s100240010116 11000330

35. Troffer-Charlier N, Doerflinger N, Metzger E, Fouquet F, Mandel JL, Aubourg P. Mirror expression of adrenoleukodystrophy and adrenoleukodystrophy related genes in mouse tissues and human cell lines. European journal of cell biology. 1998;75(3):254–64. doi: 10.1016/S0171-9335(98)80121-0 9587057

36. Strachan LR, Stevenson TJ, Freshner B, Keefe MD, Miranda Bowles D, Bonkowsky JL. A zebrafish model of X-linked adrenoleukodystrophy recapitulates key disease features and demonstrates a developmental requirement for abcd1 in oligodendrocyte patterning and myelination. Human molecular genetics. 2017;26(18):3600–14. doi: 10.1093/hmg/ddx249 28911205

37. Burn B, Brown S, Chang C. Regulation of early Xenopus development by the PIAS genes. Dev Dyn. 2011;240(9):2120–6. doi: 10.1002/dvdy.22701 21780242

38. Meraldi P. Bub1-the zombie protein that CRISPR cannot kill. The EMBO journal. 2019;38(7).

39. Lai FP, Lau ST, Wong JK, Gui H, Wang RX, Zhou T, et al. Correction of Hirschsprung-Associated Mutations in Human Induced Pluripotent Stem Cells Via Clustered Regularly Interspaced Short Palindromic Repeats/Cas9, Restores Neural Crest Cell Function. Gastroenterology. 2017;153(1):139–53.e8. doi: 10.1053/j.gastro.2017.03.014 28342760

40. Enomoto H, Crawford PA, Gorodinsky A, Heuckeroth RO, Johnson EM Jr., Milbrandt J. RET signaling is essential for migration, axonal growth and axon guidance of developing sympathetic neurons. Development (Cambridge, England). 2001;128(20):3963–74.

41. Esposito CL, D'Alessio A, de Franciscis V, Cerchia L. A Cross-Talk between TrkB and Ret Tyrosine Kinases Receptors Mediates Neuroblastoma Cells Differentiation. PloS one. 2008;3(2). doi: 10.1371/journal.pone.0001643 18286198

42. El Meskini R, Crabtree KL, Cline LB, Mains RE, Eipper BA, Ronnett GV. ATP7A (Menkes protein) functions in axonal targeting and synaptogenesis. Molecular and cellular neurosciences. 2007;34(3):409–21. doi: 10.1016/j.mcn.2006.11.018 17215139

43. Ziegler AB, Thiele C, Tenedini F, Richard M, Leyendecker P, Hoermann A, et al. Cell-Autonomous Control of Neuronal Dendrite Expansion via the Fatty Acid Synthesis Regulator SREBP. Cell reports. 2017;21(12):3346–53. doi: 10.1016/j.celrep.2017.11.069 29262315

44. Cermenati G, Audano M, Giatti S, Carozzi V, Porretta-Serapiglia C, Pettinato E, et al. Lack of sterol regulatory element binding factor-1c imposes glial Fatty Acid utilization leading to peripheral neuropathy. Cell metabolism. 2015;21(4):571–83. doi: 10.1016/j.cmet.2015.02.016 25817536

45. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell metabolism. 2008;8(3):224–36. doi: 10.1016/j.cmet.2008.07.007 18762023

46. Griffiths B, Lewis CA, Bensaad K, Ros S, Zhang Q, Ferber EC, et al. Sterol regulatory element binding protein-dependent regulation of lipid synthesis supports cell survival and tumor growth. Cancer & metabolism. 2013;1(1):3.

47. Jang J, Kang HC, Kim HS, Kim JY, Huh YJ, Kim DS, et al. Induced pluripotent stem cell models from X-linked adrenoleukodystrophy patients. Annals of neurology. 2011;70(3):402–9. doi: 10.1002/ana.22486 21721033

48. Raas Q, Gondcaille C, Hamon Y, Leoni V, Caccia C, Menetrier F, et al. CRISPR/Cas9-mediated knockout of Abcd1 and Abcd2 genes in BV-2 cells: novel microglial models for X-linked Adrenoleukodystrophy. Biochimica et biophysica acta Molecular and cell biology of lipids. 2019;1864(5):704–14. doi: 10.1016/j.bbalip.2019.02.006 30769094

49. Tang CS, Li P, Lai FP, Fu AX, Lau ST, So MT, et al. Identification of Genes Associated With Hirschsprung Disease, Based on Whole-Genome Sequence Analysis, and Potential Effects on Enteric Nervous System Development. Gastroenterology. 2018;155(6):1908–22.e5. doi: 10.1053/j.gastro.2018.09.012 30217742

50. Lake JI, Heuckeroth RO. Enteric nervous system development: migration, differentiation, and disease. American journal of physiology Gastrointestinal and liver physiology. 2013;305(1):G1–24. doi: 10.1152/ajpgi.00452.2012 23639815

51. Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014;312(18):1870–9. doi: 10.1001/jama.2014.14601 25326635

52. Thoeni C, Holzer K, Leichsenring J, Porcel C, Straub BK, Sinn HP, et al. Renal Tubular Dysgenesis in a Case of Fetus Acardius Amorphus. Case Rep Pathol. 2019;2019:5416936. doi: 10.1155/2019/5416936 31781459

53. Andreoletti P, Raas Q, Gondcaille C, Cherkaoui-Malki M, Trompier D, Savary S. Predictive Structure and Topology of Peroxisomal ATP-Binding Cassette (ABC) Transporters. International journal of molecular sciences. 2017;18(7).

54. Gourdon P, Sitsel O, Lykkegaard Karlsen J, Birk Moller L, Nissen P. Structural models of the human copper P-type ATPases ATP7A and ATP7B. Biol Chem. 2012;393(4):205–16. doi: 10.1515/hsz-2011-0249 23029640


Článek vyšel v časopise

PLOS Genetics


2020 Číslo 11

Nejčtenější v tomto čísle

Tomuto tématu se dále věnují…


Přihlášení
Zapomenuté heslo

Nemáte účet?  Registrujte se

Zapomenuté heslo

Zadejte e-mailovou adresu se kterou jste vytvářel(a) účet, budou Vám na ni zaslány informace k nastavení nového hesla.

Přihlášení

Nemáte účet?  Registrujte se