Haploinsufficiency of ARFGEF1 is associated with developmental delay, intellectual disability, and epilepsy with variable expressivity.
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
received:
03
01
2021
accepted:
07
05
2021
revised:
05
05
2021
pubmed:
12
6
2021
medline:
26
10
2021
entrez:
11
6
2021
Statut:
ppublish
Résumé
ADP ribosylation factor guanine nucleotide exchange factors (ARFGEFs) are a family of proteins implicated in cellular trafficking between the Golgi apparatus and the plasma membrane through vesicle formation. Among them is ARFGEF1/BIG1, a protein involved in axon elongation, neurite development, and polarization processes. ARFGEF1 has been previously suggested as a candidate gene for different types of epilepsies, although its implication in human disease has not been well characterized. International data sharing, in silico predictions, and in vitro assays with minigene study, western blot analyses, and RNA sequencing. We identified 13 individuals with heterozygous likely pathogenic variants in ARFGEF1. These individuals displayed congruent clinical features of developmental delay, behavioral problems, abnormal findings on brain magnetic resonance image (MRI), and epilepsy for almost half of them. While nearly half of the cohort carried de novo variants, at least 40% of variants were inherited from mildly affected parents who were clinically re-evaluated by reverse phenotyping. Our in silico predictions and in vitro assays support the contention that ARFGEF1-related conditions are caused by haploinsufficiency, and are transmitted in an autosomal dominant fashion with variable expressivity. We provide evidence that loss-of-function variants in ARFGEF1 are implicated in sporadic and familial cases of developmental delay with or without epilepsy.
Identifiants
pubmed: 34113008
doi: 10.1038/s41436-021-01218-6
pii: S1098-3600(21)05131-5
doi:
Substances chimiques
ARFGEF1 protein, human
0
Guanine Nucleotide Exchange Factors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1901-1911Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
Organisme : NHGRI NIH HHS
ID : K08 HG008986
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007526
Pays : United States
Informations de copyright
© 2021. The Author(s), under exclusive licence to the American College of Medical Genetics and Genomics.
Références
Muro, S. Alterations in cellular processes involving vesicular trafficking and implications in drug delivery. Biomimetics. 3, 19. https://doi.org/10.3390/biomimetics3030019 (2018).
doi: 10.3390/biomimetics3030019
pmcid: 6352689
Aridor, M. & Hannan, L. A. Traffic jams II: an update of diseases of intracellular transport. Traffic. 3, 781–790, https://doi.org/10.1034/j.1600-0854.2002.31103.x (2002).
doi: 10.1034/j.1600-0854.2002.31103.x
pubmed: 12383344
Aridor, M. Visiting the ER: the endoplasmic reticulum as a target for therapeutics in traffic related diseases. Adv. Drug Deliv. Rev. 59, 759–781, https://doi.org/10.1016/j.addr.2007.06.002 (2007).
doi: 10.1016/j.addr.2007.06.002
pubmed: 17681635
Wright, J., Kahn, R. A. & Sztul, E. Regulating the large Sec7 ARF guanine nucleotide exchange factors: the when, where and how of activation. Cell. Mol. Life Sci. 71, 3419–3438, https://doi.org/10.1007/s00018-014-1602-7 (2014).
doi: 10.1007/s00018-014-1602-7
pubmed: 24728583
pmcid: 4861048
Cherfils, J. et al. Structure of the Sec 7 domain of the Arf exchange factor ARNO. Nature. 392, 101–105, https://doi.org/10.1038/32210 (1998).
doi: 10.1038/32210
pubmed: 9510256
Mansour, S. J., Skaug, J., Zhao, X. H., Giordano, J., Scherer, S. W. & Melancon, P. p200 ARF-GEP1: a Golgi-localized guanine nucleotide exchange protein whose Sec7 domain is targeted by the drug brefeldin A. Proc. Natl. Acad. Sci. USA 96, 7968–7973, https://doi.org/10.1073/pnas.96.14.7968 (1999).
doi: 10.1073/pnas.96.14.7968
pubmed: 10393931
pmcid: 22171
Boal, F. & Stephens, D. J. Specific functions of BIG1 and BIG2 in endomembrane organization. PLoS One. 5, e9898. https://doi.org/10.1371/journal.pone.0009898 (2010).
doi: 10.1371/journal.pone.0009898
pubmed: 20360857
pmcid: 2845624
Zhao, X., Lasell, T. K. R. & Melançon, P. Localization of large ADP-ribosylation factor-guanine nucleotide exchange factors to different Golgi compartments: evidence for distinct functions in protein traffic. Mol. Biol. Cell. 13, 119–133, https://doi.org/10.1091/mbc.01-08-0420 (2002).
doi: 10.1091/mbc.01-08-0420
pubmed: 11809827
pmcid: 65077
Zhou, C. et al. BIG1, a brefeldin A-inhibited guanine nucleotide-exchange protein regulates neurite development via PI3K-AKT and ERK signaling pathways. Neuroscience. 254, 361–368, https://doi.org/10.1016/j.neuroscience.2013.09.045 (2013).
doi: 10.1016/j.neuroscience.2013.09.045
pubmed: 24090963
Addis, L. et al. Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses. J. Med. Genet. 55, 607–616, https://doi.org/10.1136/jmedgenet-2018-105319 (2018).
doi: 10.1136/jmedgenet-2018-105319
pubmed: 29789371
Wallace, R. H., Berkovic, S. F., Howell, R. A., Sutherland, G. R. & Mulley, J. C. Suggestion of a major gene for familial febrile convulsions mapping to 8q 13-21. J. Med. Genet. 33, 308–312, https://doi.org/10.1136/jmg.33.4.308 (1996).
doi: 10.1136/jmg.33.4.308
pubmed: 8730286
pmcid: 1050580
Piro, R. M., Molineris, I., Ala U. & Di Cunto, F. Evaluation of candidate genes from orphan FEB and GEFS+ loci by analysis of human brain gene expression atlases. PLoS One. 6, e23149, https://doi.org/10.1371/journal.pone.0023149 (2011).
doi: 10.1371/journal.pone.0023149
pubmed: 21858011
pmcid: 3157479
Appenzeller, S. et al. De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am. J. Hum. Genet. 95, 360–370, https://doi.org/10.1016/j.ajhg.2014.08.013 (2014).
doi: 10.1016/j.ajhg.2014.08.013
Takata, A. et al. Comprehensive analysis of coding variants highlights genetic complexity in developmental and epileptic encephalopathy. Nat. Commun. 10, 2506, https://doi.org/10.1038/s41467-019-10482-9 (2019).
doi: 10.1038/s41467-019-10482-9
pubmed: 31175295
pmcid: 6555845
Teoh, J. J. et al. Arfgef1 haploinsufficiency in mice alters neuronal endosome composition and decreases membrane surface postsynaptic GABAA receptors. Neurobiol. Dis. 134, 104632, https://doi.org/10.1016/j.nbd.2019.104632 (2020).
doi: 10.1016/j.nbd.2019.104632
pubmed: 31678406
Teoh, J. J. et al. BIG1 is required for the survival of deep layer neurons, neuronal polarity, and the formation of axonal tracts between the thalamus and neocortex in developing brain. PLoS One. 12, 1–24, https://doi.org/10.1371/journal.pone.0175888 (2017).
doi: 10.1371/journal.pone.0175888
Madeira, F. et al. The EMBL-EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res. 47, W636–W641, https://doi.org/10.1093/nar/gkz268 (2019).
doi: 10.1093/nar/gkz268
pubmed: 30976793
pmcid: 6602479
Soukarieh, O. et al. Exonic splicing mutations are more prevalent than currently estimated and can be predicted by using in silico tools. PLoS Genet. 12, 1–26, https://doi.org/10.1371/journal.pgen.1005756 (2016).
doi: 10.1371/journal.pgen.1005756
Da Costa, R. et al. Neutralization of HSF1 in cells from PIK3CA-related overgrowth spectrum patients blocks abnormal proliferation. Biochem. Biophys. Res. Commun.530, 520–526. https://doi.org/10.1016/j.bbrc.2020.04.146 (2020).
doi: 10.1016/j.bbrc.2020.04.146
pubmed: 32620236
Wiel, L., Baakman, C., Gilissen, D., Veltman, J. A., Vriend, G. & Gilissen, C. MetaDome: pathogenicity analysis of genetic variants through aggregation of homologous human protein domains. Hum. Mutat. 40, 1030–1038, https://doi.org/10.1002/humu.23798 (2019).
doi: 10.1002/humu.23798
pubmed: 31116477
pmcid: 6772141
Rentzsch, P., Witten, D., Cooper, G. M., Shendure, J. & Kircher, M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 47, D886–D894, https://doi.org/10.1093/nar/gky1016 (2019).
doi: 10.1093/nar/gky1016
pubmed: 30371827
Adzhubei, I., Jordan, D. M. & Sunyaev, S. R. Predicting functional effect of human missense mutations using PolyPhen-2. Curr. Protoc. Hum. Genet. 76, 7.20.1–7.20.41. https://doi.org/10.1002/0471142905.hg0720s76 (2013).
doi: 10.1002/0471142905.hg0720s76
Cooper, G. M., Stone, E. A., Asimenos, G., Green, E. D., Batzoglou, S. & Sidow, A. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 15, 901–13, https://doi.org/10.1101/gr.3577405 (2005).
doi: 10.1101/gr.3577405
pubmed: 15965027
pmcid: 1172034
Sobreira, N., Schiettecatte, F., Valle, D. & Hamosh, A. GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum. Mutat. 36, 928–930, https://doi.org/10.1002/humu.22844 (2015).
doi: 10.1002/humu.22844
pubmed: 26220891
pmcid: 4833888
Lochmüller, H. et al. RD-Connect, NeurOmics and EURenOmics: Collaborative European initiative for rare diseases. Eur. J. Hum. Genet. 26, 778–785, https://doi.org/10.1038/s41431-018-0115-5 (2018).
doi: 10.1038/s41431-018-0115-5
pubmed: 29487416
pmcid: 5974013
Ferry, Q. et al. Diagnostically relevant facial gestalt information from ordinary photos. Elife. 3 e02020, https://doi.org/10.7554/eLife.02020.001 (2014).
doi: 10.7554/eLife.02020.001
pubmed: 24963138
pmcid: 4067075
GitHub. johnwmillr/Facer: Simple face averaging in Python. https://github.com/johnwmillr/Facer (2020).
Nagy, E. & Maquat, L. E. A rule for termination-codon position within intron-containing genes: When nonsense affects RNA abundance. Trends Biochem. Sci. 23, 198–199, https://doi.org/10.1016/S0968-0004(98)01208-0 (1998).
doi: 10.1016/S0968-0004(98)01208-0
pubmed: 9644970
Bateman, A. et al. UniProt: a hub for protein information. Nucleic Acids Res. 43, D204–D212, https://doi.org/10.1093/nar/gku989 (2015).
doi: 10.1093/nar/gku989
Karczewski, K. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 581, 434–443, https://doi.org/10.1038/s41586-020-2308-7 (2020).
doi: 10.1038/s41586-020-2308-7
pubmed: 32461654
pmcid: 7334197
Li, C. et al. BIG1, a brefeldin A-inhibited guanine nucleotide-exchange factor, is required for GABA-gated Cl- influx through regulation of GABA A receptor trafficking. Mol. Neurobiol. 49, 808–819, https://doi.org/10.1007/s12035-013-8558-8 (2014).
doi: 10.1007/s12035-013-8558-8
pubmed: 24198228
Ramaen, O. et al. Interactions between conserved domains within homodimers in the BIG1, BIG2, and GBF1 Arf guanine nucleotide exchange factors. J. Biol. Chem. 282, 28834–28842, https://doi.org/10.1074/jbc.M705525200 (2007).
doi: 10.1074/jbc.M705525200
pubmed: 17640864
Sheen, V. L. et al. Mutations in ARFGEF2 implicate vesicle trafficking in neural progenitor proliferation and migration in the human cerebral cortex. Nat. Genet. 36, 69–76, https://doi.org/10.1038/ng1276 (2004).
doi: 10.1038/ng1276
pubmed: 14647276
Liu, W., Yan, B., An, D., Xiao, J., Hu, F. & Zhou, D. Sporadic periventricular nodular heterotopia: classification, phenotype and correlation with Filamin A mutations. Epilepsy Res. 133, 33–40, https://doi.org/10.1016/j.eplepsyres.2017.03.005 (2017).
doi: 10.1016/j.eplepsyres.2017.03.005
pubmed: 28411558
Zhang, J., Neal, J., Lian, G., Shi, B., Ferland, R. J. & Sheen, V. Brefeldin A-inhibited guanine exchange factor 2 regulates Filamin a phosphorylation and neuronal migration. J. Neurosci. 32, 12619–12629, https://doi.org/10.1523/JNEUROSCI.1063-12.2012 (2012).
doi: 10.1523/JNEUROSCI.1063-12.2012
pubmed: 22956851
pmcid: 3478955
Le, K., Li, C. C., Ye, G., Moss, J. & Vaughan, M. Arf guanine nucleotide-exchange factors BIG1 and BIG2 regulate nonmuscle myosin IIA activity by anchoring myosin phosphatase complex. Proc. Natl. Acad. Sci. USA. 34, E3162–E3170. https://doi.org/10.1073/pnas.1312531110 (2013).
doi: 10.1073/pnas.1312531110
Lonsdale, J. et al. The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585, https://doi.org/10.1038/ng.2653 (2013).
doi: 10.1038/ng.2653
Uhlen, M. et al. Tissue-based map of the human proteome. Science. 347, 1260419–1260419, https://doi.org/10.1126/science.1260419 (2015).
doi: 10.1126/science.1260419
pubmed: 25613900
pmcid: 25613900
Duan, X., Zhang, H. L., Pan, M. H., Zhang, Y. & Sun, S. C. Vesicular transport protein Arf6 modulates cytoskeleton dynamics for polar body extrusion in mouse oocyte meiosis. Biochim. Biophys. Acta Mol. Cell. Res. 1865, 455–462, https://doi.org/10.1016/j.bbamcr.2017.11.016 (2018).
doi: 10.1016/j.bbamcr.2017.11.016
pubmed: 29208529
Wang, S., Hu, J., Guo, X., Liu, J. X. & Gao, S. ADP-ribosylation factor 1 regulates asymmetric cell division in female meiosis in the mouse1. Biol. Reprod. 80, 555–62, https://doi.org/10.1095/biolreprod.108.073197 (2009).
doi: 10.1095/biolreprod.108.073197
pubmed: 19005166