Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity

Autoři: Zhengzheng S. Liang aff001;  Irene Cimino aff002;  Binnaz Yalcin aff003;  Narayanan Raghupathy aff004;  Valerie E. Vancollie aff001;  Ximena Ibarra-Soria aff005;  Helen V. Firth aff006;  Debra Rimmington aff002;  I. Sadaf Farooqi aff007;  Christopher J. Lelliott aff001;  Steven C. Munger aff004;  Stephen O’Rahilly aff002;  Anne C. Ferguson-Smith aff008;  Anthony P. Coll aff002;  Darren W. Logan aff001
Působiště autorů: Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, United Kingdom aff001;  MRC Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom aff002;  Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Université de Strasbourg, France aff003;  The Jackson Laboratory, Bar Harbor, Maine, United States of America aff004;  Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom aff005;  Department of Clinical Genetics, Addenbrooke’s Hospital, Cambridge, United Kingdom aff006;  University of Cambridge Metabolic Research Laboratories and NIHR Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, United Kingdom aff007;  Department of Genetics, University of Cambridge, Cambridge, United Kingdom aff008
Vyšlo v časopise: Trappc9 deficiency causes parent-of-origin dependent microcephaly and obesity. PLoS Genet 16(9): e32767. doi:10.1371/journal.pgen.1008916
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008916


Some imprinted genes exhibit parental origin specific expression bias rather than being transcribed exclusively from one copy. The physiological relevance of this remains poorly understood. In an analysis of brain-specific allele-biased expression, we identified that Trappc9, a cellular trafficking factor, was expressed predominantly (~70%) from the maternally inherited allele. Loss-of-function mutations in human TRAPPC9 cause a rare neurodevelopmental syndrome characterized by microcephaly and obesity. By studying Trappc9 null mice we discovered that homozygous mutant mice showed a reduction in brain size, exploratory activity and social memory, as well as a marked increase in body weight. A role for Trappc9 in energy balance was further supported by increased ad libitum food intake in a child with TRAPPC9 deficiency. Strikingly, heterozygous mice lacking the maternal allele (70% reduced expression) had pathology similar to homozygous mutants, whereas mice lacking the paternal allele (30% reduction) were phenotypically normal. Taken together, we conclude that Trappc9 deficient mice recapitulate key pathological features of TRAPPC9 mutations in humans and identify a role for Trappc9 and its imprinting in controlling brain development and metabolism.

Klíčová slova:

Animal sociality – Body weight – Gene expression – Genetically modified animals – Heterozygosity – Homozygosity – Mice – Mouse models


1. Crowley JJ, Zhabotynsky V, Sun W, Huang S, Pakatci IK, Kim Y, et al. Analyses of allele-specific gene expression in highly divergent mouse crosses identifies pervasive allelic imbalance. Nat Genet. 2015 Apr;47(4):353–60. doi: 10.1038/ng.3222 25730764

2. Pinter SF, Colognori D, Beliveau BJ, Sadreyev RI, Payer B, Yildirim E, et al. Allelic Imbalance Is a Prevalent and Tissue-Specific Feature of the Mouse Transcriptome. Genetics. 2015 Jun;200(2):537–49. doi: 10.1534/genetics.115.176263 25858912

3. Savova V, Vigneau S, Gimelbrant AA. Autosomal monoallelic expression: genetics of epigenetic diversity? Curr Opin Genet Dev. 2013 Dec;23(6):642–8. doi: 10.1016/j.gde.2013.09.001 24075575

4. Bartolomei MS, Ferguson-Smith AC. Mammalian genomic imprinting. Cold Spring Harb Perspect Biol. 2011 Jul 1;3(7).

5. Cleaton MA, Edwards CA, Ferguson-Smith AC. Phenotypic outcomes of imprinted gene models in mice: elucidation of pre- and postnatal functions of imprinted genes. Annu Rev Genomics Hum Genet. 2014;15:93–126. doi: 10.1146/annurev-genom-091212-153441 24898037

6. Perez JD, Rubinstein ND, Dulac C. New Perspectives on Genomic Imprinting, an Essential and Multifaceted Mode of Epigenetic Control in the Developing and Adult Brain. Annu Rev Neurosci. 2016 Jul 8;39:347–84. doi: 10.1146/annurev-neuro-061010-113708 27145912

7. Garfield AS, Cowley M, Smith FM, Moorwood K, Stewart-Cox JE, Gilroy K, et al. Distinct physiological and behavioural functions for parental alleles of imprinted Grb10. Nature. 2011 Jan 27;469(7331):534–8. doi: 10.1038/nature09651 21270893

8. Rienecker KDA, Chavasse AT, Moorwood K, Ward A, Isles AR. Detailed analysis of paternal knockout Grb10 mice suggests effects on stability of social behavior, rather than social dominance. Genes Brain Behav. 2020 Jan;19(1):e12571. doi: 10.1111/gbb.12571 30932322

9. Blagitko N, Mergenthaler S, Schulz U, Wollmann HA, Craigen W, Eggermann T, et al. Human GRB10 is imprinted and expressed from the paternal and maternal allele in a highly tissue- and isoform-specific fashion. Hum Mol Genet. 2000 Jul 1;9(11):1587–95. doi: 10.1093/hmg/9.11.1587 10861285

10. Monk D, Arnaud P, Frost J, Hills FA, Stanier P, Feil R, et al. Reciprocal imprinting of human GRB10 in placental trophoblast and brain: evolutionary conservation of reversed allelic expression. Hum Mol Genet. 2009 Aug 15;18(16):3066–74. doi: 10.1093/hmg/ddp248 19487367

11. Yoshihashi H, Maeyama K, Kosaki R, Ogata T, Tsukahara M, Goto Y, et al. Imprinting of human GRB10 and its mutations in two patients with Russell-Silver syndrome. Am J Hum Genet. 2000 Aug;67(2):476–82. doi: 10.1086/302997 10856193

12. Babak T, DeVeale B, Tsang EK, Zhou Y, Li X, Smith KS, et al. Genetic conflict reflected in tissue-specific maps of genomic imprinting in human and mouse. Nat Genet. 2015 May;47(5):544–9. doi: 10.1038/ng.3274 25848752

13. Perez JD, Rubinstein ND, Fernandez DE, Santoro SW, Needleman LA, Ho-Shing O, et al. Quantitative and functional interrogation of parent-of-origin allelic expression biases in the brain. Elife. 2015 Jul 3;4:e07860. doi: 10.7554/eLife.07860 26140685

14. Kishino T, Lalande M, Wagstaff J. UBE3A/E6-AP mutations cause Angelman syndrome. Nat Genet. 1997 Jan;15(1):70–3. doi: 10.1038/ng0197-70 8988171

15. Shi SQ, Bichell TJ, Ihrie RA, Johnson CH. Ube3a imprinting impairs circadian robustness in Angelman syndrome models. Curr Biol. 2015 Mar 2;25(5):537–45. doi: 10.1016/j.cub.2014.12.047 25660546

16. Sun J, Zhu G, Liu Y, Standley S, Ji A, Tunuguntla R, et al. UBE3A Regulates Synaptic Plasticity and Learning and Memory by Controlling SK2 Channel Endocytosis. Cell Rep. 2015 Jul 21;12(3):449–61. doi: 10.1016/j.celrep.2015.06.023 26166566

17. Mardirossian S, Rampon C, Salvert D, Fort P, Sarda N. Impaired hippocampal plasticity and altered neurogenesis in adult Ube3a maternal deficient mouse model for Angelman syndrome. Exp Neurol. 2009 Dec;220(2):341–8. doi: 10.1016/j.expneurol.2009.08.035 19782683

18. Vu TH, Hoffman AR. Imprinting of the Angelman syndrome gene, UBE3A, is restricted to brain. Nat Genet. 1997 Sep;17(1):12–3. doi: 10.1038/ng0997-12 9288087

19. Bonthuis PJ, Huang WC, Stacher Horndli CN, Ferris E, Cheng T, Gregg C. Noncanonical Genomic Imprinting Effects in Offspring. Cell Rep. 2015 Aug 11;12(6):979–91. doi: 10.1016/j.celrep.2015.07.017 26235621

20. Wang X, Sun Q, McGrath SD, Mardis ER, Soloway PD, Clark AG. Transcriptome-wide identification of novel imprinted genes in neonatal mouse brain. PLoS One. 2008;3(12):e3839. doi: 10.1371/journal.pone.0003839 19052635

21. DeVeale B, van der Kooy D, Babak T. Critical evaluation of imprinted gene expression by RNA-Seq: a new perspective. PLoS Genet. 2012;8(3):e1002600. doi: 10.1371/journal.pgen.1002600 22479196

22. Barrowman J, Bhandari D, Reinisch K, Ferro-Novick S. TRAPP complexes in membrane traffic: convergence through a common Rab. Nat Rev Mol Cell Biol. 2010 Nov;11(11):759–63. doi: 10.1038/nrm2999 20966969

23. Hu WH, Pendergast JS, Mo XM, Brambilla R, Bracchi-Ricard V, Li F, et al. NIBP, a novel NIK and IKK(beta)-binding protein that enhances NF-(kappa)B activation. J Biol Chem. 2005 Aug 12;280(32):29233–41. doi: 10.1074/jbc.M501670200 15951441

24. Lein ES, Hawrylycz MJ, Ao N, Ayres M, Bensinger A, Bernard A, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007 Jan 11;445(7124):168–76. doi: 10.1038/nature05453 17151600

25. Mochida GH, Mahajnah M, Hill AD, Basel-Vanagaite L, Gleason D, Hill RS, et al. A truncating mutation of TRAPPC9 is associated with autosomal-recessive intellectual disability and postnatal microcephaly. Am J Hum Genet. 2009 Dec;85(6):897–902. doi: 10.1016/j.ajhg.2009.10.027 20004763

26. Mir A, Kaufman L, Noor A, Motazacker MM, Jamil T, Azam M, et al. Identification of mutations in TRAPPC9, which encodes the NIK- and IKK-beta-binding protein, in nonsyndromic autosomal-recessive mental retardation. Am J Hum Genet. 2009 Dec;85(6):909–15. doi: 10.1016/j.ajhg.2009.11.009 20004765

27. Marangi G, Leuzzi V, Manti F, Lattante S, Orteschi D, Pecile V, et al. TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype. Eur J Hum Genet. 2013 Feb;21(2):229–32. doi: 10.1038/ejhg.2012.79 22549410

28. Philippe O, Rio M, Carioux A, Plaza JM, Guigue P, Molinari F, et al. Combination of linkage mapping and microarray-expression analysis identifies NF-kappaB signaling defect as a cause of autosomal-recessive mental retardation. Am J Hum Genet. 2009 Dec;85(6):903–8. doi: 10.1016/j.ajhg.2009.11.007 20004764

29. Abou Jamra R, Wohlfart S, Zweier M, Uebe S, Priebe L, Ekici A, et al. Homozygosity mapping in 64 Syrian consanguineous families with non-specific intellectual disability reveals 11 novel loci and high heterogeneity. Eur J Hum Genet. 2011 Nov;19(11):1161–6. doi: 10.1038/ejhg.2011.98 21629298

30. Kakar N, Goebel I, Daud S, Nurnberg G, Agha N, Ahmad A, et al. A homozygous splice site mutation in TRAPPC9 causes intellectual disability and microcephaly. Eur J Med Genet. 2012 Dec;55(12):727–31. doi: 10.1016/j.ejmg.2012.08.010 22989526

31. Hnoonual A, Graidist P, Kritsaneepaiboon S, Limprasert P. Novel Compound Heterozygous Mutations in the TRAPPC9 Gene in Two Siblings With Autism and Intellectual Disability. Front Genet. 2019;10:61. doi: 10.3389/fgene.2019.00061 30853973

32. Court F, Camprubi C, Garcia CV, Guillaumet-Adkins A, Sparago A, Seruggia D, et al. The PEG13-DMR and brain-specific enhancers dictate imprinted expression within the 8q24 intellectual disability risk locus. Epigenetics Chromatin. 2014 Mar 25;7(1):5. doi: 10.1186/1756-8935-7-5 24667089

33. Tirindelli R, Dibattista M, Pifferi S, Menini A. From pheromones to behavior. Physiol Rev. 2009 Jul;89(3):921–56. doi: 10.1152/physrev.00037.2008 19584317

34. Whitlock KE. Developing a sense of scents: plasticity in olfactory placode formation. Brain Res Bull. 2008 Mar 18;75(2–4):340–7. doi: 10.1016/j.brainresbull.2007.10.054 18331896

35. Gregg C, Zhang J, Weissbourd B, Luo S, Schroth GP, Haig D, et al. High-resolution analysis of parent-of-origin allelic expression in the mouse brain. Science. 2010 Aug 6;329(5992):643–8. doi: 10.1126/science.1190830 20616232

36. Munger SC, Raghupathy N, Choi K, Simons AK, Gatti DM, Hinerfeld DA, et al. RNA-Seq alignment to individualized genomes improves transcript abundance estimates in multiparent populations. Genetics. 2014 Sep;198(1):59–73. doi: 10.1534/genetics.114.165886 25236449

37. Raghupathy N, Choi K, Vincent MJ, Beane GL, Sheppard KS, Munger SC, et al. Hierarchical analysis of RNA-seq reads improves the accuracy of allele-specific expression. Bioinformatics. 2018 Jul 1;34(13):2177–84. doi: 10.1093/bioinformatics/bty078 29444201

38. Ibarra-Soria X, Nakahara TS, Lilue J, Jiang Y, Trimmer C, Souza MA, et al. Variation in olfactory neuron repertoires is genetically controlled and environmentally modulated. Elife. 2017 Apr 25;6.

39. Wang X, Miller DC, Harman R, Antczak DF, Clark AG. Paternally expressed genes predominate in the placenta. Proc Natl Acad Sci U S A. 2013 Jun 25;110(26):10705–10. doi: 10.1073/pnas.1308998110 23754418

40. Morison IM, Paton CJ, Cleverley SD. The imprinted gene and parent-of-origin effect database. Nucleic Acids Res. 2001 Jan 1;29(1):275–6. doi: 10.1093/nar/29.1.275 11125110

41. Blake A, Pickford K, Greenaway S, Thomas S, Pickard A, Williamson CM, et al. MouseBook: an integrated portal of mouse resources. Nucleic Acids Res. 2010 Jan;38(Database issue):D593–9. doi: 10.1093/nar/gkp867 19854936

42. Smith RJ, Dean W, Konfortova G, Kelsey G. Identification of novel imprinted genes in a genome-wide screen for maternal methylation. Genome Res. 2003 Apr;13(4):558–69. doi: 10.1101/gr.781503 12670997

43. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, et al. A conditional knockout resource for the genome-wide study of mouse gene function. Nature. 2011 Jun 15;474(7351):337–42. doi: 10.1038/nature10163 21677750

44. Ashwal S, Michelson D, Plawner L, Dobyns WB, Quality Standards Subcommittee of the American Academy of N, the Practice Committee of the Child Neurology S. Practice parameter: Evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2009 Sep 15;73(11):887–97. doi: 10.1212/WNL.0b013e3181b783f7 19752457

45. Sanchez-Andrade G, Kendrick KM. Roles of alpha- and beta-estrogen receptors in mouse social recognition memory: effects of gender and the estrous cycle. Horm Behav. 2011 Jan;59(1):114–22. doi: 10.1016/j.yhbeh.2010.10.016 21056567

46. Arnaud P, Hata K, Kaneda M, Li E, Sasaki H, Feil R, et al. Stochastic imprinting in the progeny of Dnmt3L-/- females. Hum Mol Genet. 2006 Feb 15;15(4):589–98. doi: 10.1093/hmg/ddi475 16403808

47. Philippe O, Rio M, Malan V, Van Esch H, Baujat G, Bahi-Buisson N, et al. NF-kappaB signalling requirement for brain myelin formation is shown by genotype/MRI phenotype correlations in patients with Xq28 duplications. Eur J Hum Genet. 2013 Feb;21(2):195–9. doi: 10.1038/ejhg.2012.140 22805531

48. Dalgaard K, Landgraf K, Heyne S, Lempradl A, Longinotto J, Gossens K, et al. Trim28 Haploinsufficiency Triggers Bi-stable Epigenetic Obesity. Cell. 2016 Jan 28;164(3):353–64. doi: 10.1016/j.cell.2015.12.025 26824653

49. Byerly MS, Swanson RD, Wong GW, Blackshaw S. Stage-specific inhibition of TrkB activity leads to long-lasting and sexually dimorphic effects on body weight and hypothalamic gene expression. PLoS One. 2013;8(11):e80781. doi: 10.1371/journal.pone.0080781 24312242

50. Ito Y, Banno R, Shibata M, Adachi K, Hagimoto S, Hagiwara D, et al. GABA type B receptor signaling in proopiomelanocortin neurons protects against obesity, insulin resistance, and hypothalamic inflammation in male mice on a high-fat diet. J Neurosci. 2013 Oct 23;33(43):17166–73. doi: 10.1523/JNEUROSCI.0897-13.2013 24155320

51. Larder R, Sim MFM, Gulati P, Antrobus R, Tung YCL, Rimmington D, et al. Obesity-associated gene TMEM18 has a role in the central control of appetite and body weight regulation. Proc Natl Acad Sci U S A. 2017 Aug 29;114(35):9421–6. doi: 10.1073/pnas.1707310114 28811369

52. Palmer BF, Clegg DJ. The sexual dimorphism of obesity. Mol Cell Endocrinol. 2015 Feb 15;402:113–9. doi: 10.1016/j.mce.2014.11.029 25578600

53. White JK, Gerdin AK, Karp NA, Ryder E, Buljan M, Bussell JN, et al. Genome-wide generation and systematic phenotyping of knockout mice reveals new roles for many genes. Cell. 2013 Jul 18;154(2):452–64. doi: 10.1016/j.cell.2013.06.022 23870131

54. Keane TM, Goodstadt L, Danecek P, White MA, Wong K, Yalcin B, et al. Mouse genomic variation and its effect on phenotypes and gene regulation. Nature. 2011 Sep 14;477(7364):289–94. doi: 10.1038/nature10413 21921910

55. Hebenstreit D, Fang M, Gu M, Charoensawan V, van Oudenaarden A, Teichmann SA. RNA sequencing reveals two major classes of gene expression levels in metazoan cells. Mol Syst Biol. 2011 Jun 7;7:497. doi: 10.1038/msb.2011.28 21654674

56. Chen X, Weaver J, Bove BA, Vanderveer LA, Weil SC, Miron A, et al. Allelic imbalance in BRCA1 and BRCA2 gene expression is associated with an increased breast cancer risk. Hum Mol Genet. 2008 May 1;17(9):1336–48. doi: 10.1093/hmg/ddn022 18204050

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