[en] Congenital hydrocephalus is a potentially devastating, highly heterogeneous condition whose genetic subset remains incompletely known. We here report a consanguineous family where three fetuses presented with brain ventriculomegaly and limb contractures and shared a very rare homozygous variant of KIDINS220, consisting of an in-frame deletion of three amino acids adjacent to the fourth transmembrane domain. Fetal brain imaging and autopsy showed major ventriculomegaly, reduced brain mass, and with no histomorphologic abnormalities. We demonstrate that the binding of KIDINS220 to TrkA is diminished by the deletion mutation. This family is the second that associates a KIDINS220 genetic variant with human ventriculomegaly and limb contractures, validating causality of the gene and indicating TrkA as a likely mediator of the phenotype.
Disciplines :
Genetics & genetic processes
Author, co-author :
JACQUEMIN, VALERIE ; Centre Hospitalier Universitaire de Liège - CHU > > Service de génétique ; IRIBHM, Université Libre de Bruxelles, 1070 Brussels, Belgium
Antoine, Mathieu; IRIBHM, Université Libre de Bruxelles, 1070 Brussels, Belgium
Massart, Annick; IRIBHM, Université Libre de Bruxelles, 1070 Brussels, Belgium ; Department of Nephrology, Hôpital Universitaire d'Anvers, 2650 Edegem, Belgium
Desir, Julie; Human Genetics Center, Institute of Pathology and Genetics, 6041 Charleroi, Belgium
Perazzolo, Camille; IRIBHM, Université Libre de Bruxelles, 1070 Brussels, Belgium
Cassart, Marie; Department of Gynecology and Obstetrics, Hôpitaux Iris Sud, 1050 Brussels, Belgium
Thomas, Dominique; Department of Gynecology and Obstetrics, Hôpitaux Iris Sud, 1050 Brussels, Belgium
Segers, Valérie; Department of Anatomopathology, CHU Brugmann, 1020 Brussels, Belgium
Lecomte, Sophie; Department of Anatomopathology, CHU Brugmann, 1020 Brussels, Belgium
Abramowicz, Marc; IRIBHM, Université Libre de Bruxelles, 1070 Brussels, Belgium ; Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland
Pirson, Isabelle; IRIBHM, Université Libre de Bruxelles, 1070 Brussels, Belgium
Language :
English
Title :
TrkA mediates effect of novel KIDINS220 mutation in human brain ventriculomegaly.
Persson, E.-K., Anderson, S., Wiklund, L.-M. and Uvebrant,P. (2007) Hydrocephalus in children born in 1999-2002: epidemiology, outcome and ophthalmological findings. ChildsNerv. Syst., 23, 1111-1118.
Mori, K., Shimada, J., Kurisaka, M., Sato, K. and Watanabe,K. (1995) Classification of hydrocephalus and outcome oftreatment. Brain and Development, 17, 338-348.
Nagaraj, U.D. and Kline-Fath, B.M. (2020) Imaging diagnosisof ventriculomegaly: fetal, neonatal, and pediatric. ChildsNerv. Syst., 36, 1669-1679.
Chi, J.H., Fullerton, H.J. and Gupta, N. (2005) Time trends anddemographics of deaths from congenital hydrocephalus inchildren in the United States: National Center for HealthStatistics data, 1979 to 1998. J. Neurosurg., 103, 113-118.
Verhagen, J.M., Schrander-Stumpel, C.T., Krapels, I.P., de DieSmulders, C.E.M., van Lint, F.H.M., Willekes, C., Weber, J.W.,Gavilanes, A.W.D., Macville, M.V.E. et al. (2011) Congenital hydrocephalus in clinical practice: a genetic diagnosticapproach. Eur. J. Med. Genet., 54, e542-e547.
Rosenthal, A., Jouet, M. and Kenwrick, S. (1992) Aberrantsplicing of neural cell adhesion molecule L1 mRNA in afamily with X-linked hydrocephalus. Nat. Genet., 2, 107-112.
Tarpey, P.S., Stevens, C., Teague, J., Edkins, S., O (tm)Meara, S.,Avis, T., Barthorpe, S., Buck, G., Butler, A., Cole, J. et al. (2006)Mutations in the gene encoding the sigma 2 subunit of theadaptor protein 1 complex, AP1S2, cause X-linked mentalretardation. Am. J. Hum. Genet., 79, 1119-1124.
Al-Dosari, M.S., Al-Owain, M., Tulbah, M., Kurdi, W., Adly, N.,Al-Hemidan, A., Masoodi, T.A., Albash, B. and Alkuraya, F.S.(2013) Mutation in MPDZ causes severe congenital hydrocephalus. J. Med. Genet., 50, 54-58.
Drielsma, A., Jalas, C., Simonis, N., D (c)sir, J., Simanovsky,N., Pirson, I., Elpeleg, O., Abramowicz, M. and Edvardson, S.(2012) Two novel CCDC88C mutations confirm the role ofDAPLE in autosomal recessive congenital hydrocephalus. J.Med. Genet., 49, 708-712.
Shaheen, R., Sebai, M.A., Patel, N., Ewida, N., Kurdi,W., Altweijri, I., Sogaty, S., Almardawi, E., Seidahmed, M.Z., Alnemri,A. et al. (2017) The genetic landscape of familial congenitalhydrocephalus: congenital hydrocephalus. Ann. Neurol., 81,890-897.
Furey, C.G., Choi, J., Jin, S.C., Zeng, X., Timberlake, A.T.,Nelson-Williams, C., Mansuri, M.S., Lu, Q., Duran, D., Panchagnula, S. et al. (2018) De novo mutation in genes regulating neural stem cell fate in human congenital hydrocephalus. Neuron, 99, 302-314.
Wallmeier, J., Frank, D., Shoemark, A., Nöthe-Menchen, T.,Cindric, S., Olbrich, H., Loges, N.T., Aprea, I., Dougherty, G.W.,Pennekamp, P. et al. (2019) De novo mutations in FOXJ1 resultin a motile Ciliopathy with hydrocephalus and randomization of left/right body asymmetry. Am. J. Hum. Genet., 105,1030-1039.
Mero, I.-L., Mørk, H.H., Sheng, Y., Blomhoff, A., Opheim, G.L.,Erichsen, A., Vigeland, M.D. and Selmer, K.K. (2017) Homozygous KIDINS220 loss-of-function variants in fetuses withcerebral ventriculomegaly and limb contractures. Hum. Mol.Genet., 26, 3792-3796.
Josifova, D.J., Monroe, G.R., Tessadori, F., de Graaff, E., vander Zwaag, B., Mehta, S.G., Harakalova, M., Duran, K.J.,Savelberg, S.M.C., Nijman, I.J. et al. (2016) HeterozygousKIDINS220/ARMS nonsense variants cause spastic paraplegia, intellectual disability, nystagmus, and obesity. Hum. Mol.Genet., 25, 2158-2167.
Scholz-Starke, J. and Cesca, F. (2016) Stepping out of theshade: control of neuronal activity by the scaffold proteinKidins220/ARMS. Front. Cell. Neurosci., 10.
Neubrand, V.E., Cesca, F., Benfenati, F. and Schiavo, G. (2012)Kidins220/ARMS as a functional mediator of multiple receptor signalling pathways. J. Cell Sci., 125, 1845-1854.
Kong, H., Boulter, J., Weber, J.L., Lai, C. and Chao, M.V. (2001)An evolutionarily conserved Transmembrane protein thatis a novel downstream target of Neurotrophin and Ephrinreceptors. J. Neurosci., 21, 176-185.
Ar (c)valo, J.C., Yano, H., Teng, K.K. and Chao, M.V. (2004)A unique pathway for sustained neurotrophin signaling through an ankyrin-rich membrane-spanning protein.EMBO J., 23, 2358-2368.
Chang, M.-S., Arevalo, J.C. and Chao, M.V. (2004) Ternary complex with Trk, p75, and an ankyrin-rich membrane spanningprotein. J. Neurosci. Res., 78, 186-192.
Luo, S., Chen, Y., Lai, K.-O., Ar (c)valo, J.C., Froehner, S.C.,Adams, M.E., Chao, M.V. and Ip, N.Y. (2005) α-Syntrophin regulates ARMS localization at the neuromuscular junction andenhances EphA4 signaling in an ARMS-dependent manner.J. Cell Biol., 169, 813-824.
Reichardt, L.F. (2006) Neurotrophin-regulated signallingpathways. Philos. Trans. R. Soc. B Biol. Sci., 361,1545-1564.
Gupta, V.K., You, Y., Gupta, V.B., Klistorner, A. and Graham,S.L. (2013) TrkB receptor signalling: implications in neurodegenerative, psychiatric and proliferative disorders. Int. J. Mol.Sci., 14, 10122-10142.
Haddad, Y., Adam, V. and Heger, Z. (2017) Trk receptors andNeurotrophin cross-interactions: new perspectives towardmanipulating therapeutic side-effects. Front. Mol. Neurosci.,10.
Novak, K. (2004) Getting on TRK. Nat. Rev. Cancer, 4, 920.
Holt, O., Kanno, E., Bossi, G., Booth, S., Daniele, T., Santoro, A.,Arico, M., Saegusa, C., Fukuda, M. and Griffiths, G.M. (2008)Slp1 and Slp2-a localize to the plasma membrane of CTL andcontribute to secretion from the immunological synapse.Traffic, 9, 446-457.
Cassioli, C. and Baldari, C.T. (2019) A Ciliary view of theimmunological synapse. Cell, 8, 789.
Cesca, F., Yabe, A., Spencer-Dene, B., Arrigoni, A., Al-Qatari,M., Henderson, D., Phillips, H., Koltzenburg, M., Benfenati, F.and Schiavo, G. (2011) Kidins220/ARMS is an essential modulator of cardiovascular and nervous system development.Cell Death Dis., 2, e226.
Karczewski, K.J., Francioli, L.C., Tiao, G., Cummings, B.B.,Alföldi, J., Wang, Q., Collins, R.L., Laricchia, K.M., Ganna, A.,Birnbaum, D.P. et al. (2020) The mutational constraint spectrum quantified from variation in 141,456 humans. Nature,581, 434-443.
Genic Intolerance. Genic intolerance http://genic-intolerance.org/about.jsp (accessed May 31, 2019).
Jullien, J., Guili, V., Reichardt, L.F. and Rudkin, B.B. (2002)Molecular kinetics of nerve growth factor receptor trafficking and activation. J. Biol. Chem., 277, 38700-38708.
Yamamoto, N., Yamashita, Y., Yoshioka, Y., Nishiumi, S. andAshida, H. (2016) Rapid preparation of a plasma membranefraction: western blot detection of Translocated glucosetransporter 4 from plasma membrane of muscle and adiposecells and tissues. Curr. Protoc. Protein Sci., 85, 29.18.1-29.18.12.
Terwilliger, J.D. and Ott, J. (1994) Handbook of Human GeneticLinkage. In Handbook of Human Genetic Linkage. Johns HopkinsUniversity Press, Baltimore (Md.).
Neubrand, V.E., Thomas, C., Schmidt, S., Debant, A. and Schiavo, G. (2010) Kidins220/ARMS regulates Rac1-dependentneurite outgrowth by direct interaction with the RhoGEF trio.J. Cell Sci., 123, 2111-2123.
Ar (c)valo, J.C., Waite, J., Rajagopal, R., Beyna, M., Chen, Z.-Y., Lee, F.S. and Chao, M.V. (2006) Cell survival through Trkneurotrophin receptors is differentially regulated by ubiquitination. Neuron, 50, 549-559.
Bracale, A., Cesca, F., Neubrand, V.E., Newsome, T.P., Way,M. and Schiavo, G. (2007) Kidins220/ARMS is transportedby a Kinesin-1-based mechanism likely to be involved inneuronal differentiation. Mol. Biol. Cell, 18, 142-152.
Kumar, V., Gupta, A.K., Shukla, R.K., Tripathi, V.K., Jahan, S.,Pandey, A., Srivastava, A., Agrawal, M., Yadav, S., Khanna,V. and Pant, A.B. (2015) Molecular mechanism of switching of TrkA/p75 NTR Signaling in Monocrotophos inducedneurotoxicity. Sci. Rep., 5, 14038.
López-Men (c)ndez, C., Gascón, S., Sobrado, M., Vidaurre, O.,Higuero, A., Rodríguez-Peña, A., Iglesias, T. and Díaz-Guerra,M. (2009) Kidins220/ARMS downregulation by excitotoxicactivation of NMDARs reveals its involvement in neuronalsurvival and death pathways. J. Cell Sci., 122, 3554-3565.
Friedman, W.J. (2000) Neurotrophins induce death of hippocampal neurons via the p75 receptor. J. Neurosci., 20,6340-6346.
Yoon, S.O., Casaccia-Bonnefil, P., Carter, B. and Chao, M.V.(1998) Competitive Signaling between TrkA and p75 nervegrowth factor receptors determines cell survival. J. Neurosci.,18, 3273-3281.
Cesca, F., Yabe, A., Spencer-Dene, B., Scholz-Starke, J., Medrihan, L., Maden, C.H., Gerhardt, H., Orriss, I.R., Baldelli, P., AlQatari, M. et al. (2012) Kidins220/ARMS mediates the integration of the neurotrophin and VEGF pathways in the vascularand nervous systems. Cell Death Differ., 19, 194-208.
Duerinckx, S., Jacquemin, V., Drunat, S., Vial, Y., Passemard,S., Perazzolo, C., Massart, A., Soblet, J., Racap (c), J., Desmyter,L. et al. (2020) Digenic inheritance of human primary microcephaly delineates centrosomal and non-centrosomal pathways. Hum. Mutat., 41, 512-524.
Ishida, M., Cullup, T., Boustred, C., James, C., Docker, J.,English, C., Lench, N., Copp, A.J., Moore, G.E., Greene, N.D.E.and Stanier, P. (2018) A targeted sequencing panel identifiesrare damaging variants in multiple genes in the cranialneural tube defect, anencephaly. Clin. Genet., 93, 870-879.
Kim, A., Savary, C., Dubourg, C., Carr (c), W., Mouden, C.,Hamdi-Roz (c), H., Guyodo, H., Le Douce, J., Pasquier, L., Flori,E. et al. (2019) Integrated clinical and omics approach torare diseases: novel genes and oligogenic inheritance inholoprosencephaly. Brain, 142, 35-49.
Lanuza, M.A., Just-Borr s, L., Hurtado, E., Cilleros-Mañ (c), V.,Tom s, M., Garcia, N. and Tom s, J. (2019) The impact ofkinases in amyotrophic lateral sclerosis at the neuromuscular synapse: insights into BDNF/TrkB and PKC Signaling.Cell, 8, 1578.
Seaberg, B., Henslee, G., Wang, S., Paez-Colasante, X., Landreth, G.E. and Rimer, M. (2015) Muscle-derived extracellularsignal-regulated kinases 1 and 2 are required for the maintenance of adult Myofibers and their neuromuscular junctions. Mol. Cell. Biol., 35, 1238-1253.
Bamshad, M., Van Heest, A.E. and Pleasure, D. (2009) Arthrogryposis: a review and update. J. Bone Joint Surg. Am., 91,40-46.
Wu, S.H., Ar (c)valo, J.C., Sarti, F., Tessarollo, L., Gan, W.-B.and Chao, M.V. (2009) Ankyrin repeat-rich membrane spanning/Kidins220 protein regulates dendritic branching andspine stability in vivo. Dev. Neurobiol., 69, 547-557.
BRIGHTcore. BRIGHTcore http://www.brightcore.be(accessed May 31, 2019).
Li, H. and Durbin, R. (2009) Fast and accurate short readalignment with burrows-wheeler transform. Bioinforma, 25,1754-1760.
Picard Tools - By Broad Institute. https://broadinstitute.github.io/picard/ (accessed May 31, 2019).
DePristo, M.A., Banks, E., Poplin, R., Garimella, K.V., Maguire,J.R., Hartl, C., Philippakis, A.A., del Angel, G., Rivas, M.A.,Hanna, M. et al. (2011) A framework for variation discovery and genotyping using next-generation DNA sequencingdata. Nat. Genet., 43, 491-498.
Highlander - home (Internet). https://sites.uclouvain.be/highlander/documentation.html (accessed May 31, 2019).
Lek, M., Karczewski, K.J., Minikel, E.V., Samocha, K.E., Banks,E., Fennell, T., O (tm)Donnell-Luria, A.H., Ware, J.S., Hill, A.J., Cummings, B.B. et al. (2016) Analysis of protein-coding geneticvariation in 60,706 humans. Nature, 536, 285-291.
1000 Genomes Project Consortium, Auton, A., Brooks, L.D.,Durbin, R.M., Garrison, E.P., Kang, H.M., Korbel, J.O., Marchini,J.L., McCarthy, S., McVean, G.A. and Abecasis, G.R. (2015) Aglobal reference for human genetic variation. Nature, 526,68-74.
Exome Variant Server - Search Results. https://evs.gs.washington.edu/EVS/PopStatsServlet?searchBy=Gene+Hugo&target=kidins220&x=0&y=0 (accessed Jun 4, 2019).
Genome of the Netherlands. Genome of the Netherlandshttp://www.nlgenome.nl/ (accessed June 4, 2019).
Atherosclerosis Risk in Communities. Atherosclerosis risk incommunities study description. https://sites.cscc.unc.edu/aric/desc-pub (accessed June 4, 2019).
Yates, A., Akanni, W., Amode, M.R., Barrell, D., Billis, K.,Carvalho-Silva, D., Cummins, C., Clapham, P., Fitzgerald, S.,Gil, L. et al. (2016) Ensembl 2016. Nucleic Acids Res., 44, D710-D716.
Cingolani, P., Platts, A.,Wang, L.L., Coon,M., Nguyen, T.,Wang,L., Land, S.J., Lu, X. and Ruden, D.M. (2012) A program forannotating and predicting the effects of single nucleotidepolymorphisms, SnpEff: SNPs in the genome of Drosophilamelanogaster strain w1118; iso-2; iso-3. Fly (Austin), 6,80-92.
