DLG4-related synaptopathy: a new rare brain disorder.
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:
05 2021
05 2021
Historique:
received:
16
10
2020
accepted:
15
12
2020
revised:
12
12
2020
pubmed:
19
2
2021
medline:
4
6
2021
entrez:
18
2
2021
Statut:
ppublish
Résumé
Postsynaptic density protein-95 (PSD-95), encoded by DLG4, regulates excitatory synaptic function in the brain. Here we present the clinical and genetic features of 53 patients (42 previously unpublished) with DLG4 variants. The clinical and genetic information were collected through GeneMatcher collaboration. All the individuals were investigated by local clinicians and the gene variants were identified by clinical exome/genome sequencing. The clinical picture was predominated by early onset global developmental delay, intellectual disability, autism spectrum disorder, and attention deficit-hyperactivity disorder, all of which point to a brain disorder. Marfanoid habitus, which was previously suggested to be a characteristic feature of DLG4-related phenotypes, was found in only nine individuals and despite some overlapping features, a distinct facial dysmorphism could not be established. Of the 45 different DLG4 variants, 39 were predicted to lead to loss of protein function and the majority occurred de novo (four with unknown origin). The six missense variants identified were suggested to lead to structural or functional changes by protein modeling studies. The present study shows that clinical manifestations associated with DLG4 overlap with those found in other neurodevelopmental disorders of synaptic dysfunction; thus, we designate this group of disorders as DLG4-related synaptopathy.
Identifiants
pubmed: 33597769
doi: 10.1038/s41436-020-01075-9
pii: S1098-3600(21)01446-5
doi:
Substances chimiques
DLG4 protein, human
0
Disks Large Homolog 4 Protein
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
888-899Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Références
Sheng, M. & Kim, E. The postsynaptic organization of synapses. Cold Spring Harb. Perspect. Biol. 3, a005678 (2011).
doi: 10.1101/cshperspect.a005678
Nithianantharajah, J. et al. Synaptic scaffold evolution generated components of vertebrate cognitive complexity. Nat. Neurosci. 16, 16–24 (2013).
doi: 10.1038/nn.3276
Philips, A. K. et al. X-exome sequencing in Finnish families with Intellectual Disability - Four novel mutations and two novel syndromic phenotypes. Orphanet J. Rare Dis. 9, 49 (2014).
doi: 10.1186/1750-1172-9-49
Tarpey, P. et al. Mutations in the DLG3 gene cause nonsyndromic X-linked mental retardation. Am. J. Hum. Genet. 75, 318–324 (2004).
doi: 10.1086/422703
Guo, H. et al. Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Mol. Autism 9, 64 (2018).
doi: 10.1186/s13229-018-0247-z
Xu, B., Roos, J. L., Levy, S., Van Rensburg, E. J., Gogos, J. A. & Karayiorgou, M. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat. Genet. 40, 880–885 (2008).
doi: 10.1038/ng.162
Kirov, G. et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol. Psychiatry 17, 142–153 (2012).
doi: 10.1038/mp.2011.154
Feyder, M. et al. Association of mouse Dlg4 (PSD-95) gene deletion and human DLG4 gene variation with phenotypes relevant to autism spectrum disorders and Williams’ syndrome. Am. J. Psychiatry 167, 1508–1517 (2010).
doi: 10.1176/appi.ajp.2010.10040484
Coley, A. A. & Gao, W. J. PSD-95 deficiency disrupts PFC-associated function and behavior during neurodevelopment. Sci. Rep. 9, 9486 (2019).
doi: 10.1038/s41598-019-45971-w
Winkler, D. et al. Hypersocial behavior and biological redundancy in mice with reduced expression of PSD95 or PSD93. Behav. Brain Res. 352, 35–45 (2018).
doi: 10.1016/j.bbr.2017.02.011
Rauch, A. et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study. Lancet. 380, 1674–1682 (2012).
doi: 10.1016/S0140-6736(12)61480-9
Lelieveld, S. H. et al. Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability. Nat. Neurosci. 19, 1194–1196 (2016).
doi: 10.1038/nn.4352
Fitzgerald, T. W. et al. Large-scale discovery of novel genetic causes of developmental disorders. Nature. 519, 223–228 (2015).
doi: 10.1038/nature14135
Bosch, D. G. M. et al. Novel genetic causes for cerebral visual impairment. Eur. J. Hum. Genet. 24, 660–665 (2016).
doi: 10.1038/ejhg.2015.186
Xing, J. et al. Resequencing and association analysis of Six PSD-95-related genes as possible susceptibility genes for schizophrenia and autism spectrum disorders. Sci. Rep. 6, 27491 (2016).
doi: 10.1038/srep27491
Moutton, S. et al. Truncating variants of the DLG4 gene are responsible for intellectual disability with marfanoid features. Clin. Genet. 93, 1172–1178 (2018).
Baker, S. W. et al. Automated clinical exome reanalysis reveals novel diagnoses. J. Mol. Diagn. 21, 38–48 (2019).
doi: 10.1016/j.jmoldx.2018.07.008
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 (2015).
doi: 10.1002/humu.22844
Firth, H. V. et al. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am. J. Hum. Genet. 84, 524–533 (2009).
doi: 10.1016/j.ajhg.2009.03.010
Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17, 405–424 (2015).
doi: 10.1038/gim.2015.30
Amendola, L. M. et al. Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the Clinical Sequencing Exploratory Research Consortium. Am. J. Hum. Genet. 98, 1067–1076 (2016).
doi: 10.1016/j.ajhg.2016.03.024
Coban-Akdemir, Z. et al. Identifying genes whose mutant transcripts cause dominant disease traits by potential gain-of-function alleles. Am. J. Hum. Genet. 103, 171–178 (2018).
doi: 10.1016/j.ajhg.2018.06.009
Jaganathan, K. et al. Predicting splicing from primary sequence with deep learning. Cell. 176, 535–548 (2019).
doi: 10.1016/j.cell.2018.12.015
McGee, A. W., Dakoji, S. R., Olsen, O., Bredt, D. S., Lim, W. A. & Prehoda, K. E. Structure of the SH3-guanylate kinase module from PSD-95 suggests a mechanism for regulated assembly of MAGUK scaffolding proteins. Mol. Cell 8, 1291–1301 (2001).
doi: 10.1016/S1097-2765(01)00411-7
Fomina, S. et al. Self-directed assembly and clustering of the cytoplasmic domains of inwardly rectifying Kir2.1 potassium channels on association with PSD-95. Biochim. Biophys. Acta 1808, 2374–2389 (2011).
doi: 10.1016/j.bbamem.2011.06.021
Benkert, P., Biasini, M. & Schwede, T. Toward the estimation of the absolute quality of individual protein structure models. Bioinformatics. 27, 343–350 (2011).
doi: 10.1093/bioinformatics/btq662
Krab, L. C. et al. Delineation of phenotypes and genotypes related to cohesin structural protein RAD21. Hum. Genet. 139, 575–592 (2020).
doi: 10.1007/s00439-020-02138-2
Hornbeck, P. V., Zhang, B., Murray, B., Kornhauser, J. M., Latham, V. & Skrzypek, E. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 43, D512–D520 (2015).
doi: 10.1093/nar/gku1267
Grant, S. G. N. Synapse diversity and synaptome architecture in human genetic disorders. Hum. Mol. Genet. 28, R219–R225 (2019).
doi: 10.1093/hmg/ddz178
Tristán-Noguero, A. & García-Cazorla, À. Synaptic metabolism: a new approach to inborn errors of neurotransmission. J. Inherit. Metab. Dis. 41, 1065–1075 (2018).
doi: 10.1007/s10545-018-0235-7
Zapata, J. et al. Epilepsy and intellectual disability linked protein Shrm4 interaction with GABA B Rs shapes inhibitory neurotransmission. Nat. Commun. 8, 14536 (2017).
doi: 10.1038/ncomms14536
Ung, D. C. et al. Ptchd1 deficiency induces excitatory synaptic and cognitive dysfunctions in mouse. Mol. Psychiatry 23, 1356–1367 (2017).
doi: 10.1038/mp.2017.39
Abela, L. & Kurian, M. A. Postsynaptic movement disorders: clinical phenotypes, genotypes, and disease mechanisms. J. Inherit. Metab. Dis. 41, 1077–1091 (2018).
doi: 10.1007/s10545-018-0205-0
Jang, M. et al. Coexistence of glutamatergic spine synapses and shaft synapses in substantia nigra dopamine neurons. Sci. Rep. 5, 14773 (2015).
doi: 10.1038/srep14773
Morigaki, R. & Goto, S. Postsynaptic density protein 95 in the striosome and matrix compartments of the human neostriatum. Front. Neuroanat. 9, 154 (2015).
doi: 10.3389/fnana.2015.00154
Gamss, R. P., Slasky, S. E., Bello, J. A., Miller, T. S. & Shinnar, S. Prevalence of hippocampal malrotation in a population without seizures. Am. J. Neuroradiol. 30, 1571–1573 (2009).
doi: 10.3174/ajnr.A1657
Chan, S. et al. Hippocampal malrotation is associated with prolonged febrile seizures: Results of the FEBSTAT study. Am. J. Roentgenol. 205, 1068–1074 (2015).
doi: 10.2214/AJR.14.13330
Krishnan, M. L. et al. Integrative genomics of microglia implicates DLG4 (PSD95) in the white matter development of preterm infant. Nat. Commun. 8, 428 (2017).
doi: 10.1038/s41467-017-00422-w
Ohnuma, T., Kato, H., Arai, H., Faull, R. L. M., McKenna, P. J. & Emson, P. C. Gene expression of PSD95 in prefrontal cortex and hippocampus in schizophrenia. Neuroreport. 11, 3133–3137 (2000).
doi: 10.1097/00001756-200009280-00019
Kaplanis, J. et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature 586, 757–762 (2020).
doi: 10.1038/s41586-020-2832-5