Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2023 Jan 19:14:1101087.
doi: 10.3389/fimmu.2023.1101087. eCollection 2023.

Maternal synapsin autoantibodies are associated with neurodevelopmental delay

Isabel Bünger  1   2 , Konstantin L Makridis  3   4   5   6 , Jakob Kreye  1   2   3   4   5   7 , Marc Nikolaus  3   4   5   7 , Eva Sedlin  3   4 , Tim Ullrich  3   4 , Christian Hoffmann  2 , Johannes Vincent Tromm  2 , Helle Foverskov Rasmussen  1   2 , Dragomir Milovanovic  2 , Markus Höltje  8 , Harald Prüss  1   2 , Angela M Kaindl  3   4   5   6
Affiliations

Maternal synapsin autoantibodies are associated with neurodevelopmental delay

Isabel Bünger et al. Front Immunol. .

Abstract

Maternal autoantibodies can be transmitted diaplacentally, with potentially deleterious effects on neurodevelopment. Synapsin 1 (SYN1) is a neuronal protein that is important for synaptic communication and neuronal plasticity. While monoallelic loss of function (LoF) variants in the SYN1 gene result in X-linked intellectual disability (ID), learning disabilities, epilepsy, behavioral problems, and macrocephaly, the effect of SYN1 autoantibodies on neurodevelopment remains unclear. We recruited a clinical cohort of 208 mothers and their children with neurologic abnormalities and analyzed the role of maternal SYN1 autoantibodies. We identified seropositivity in 9.6% of mothers, and seropositivity was associated with an increased risk for ID and behavioral problems. Furthermore, children more frequently had epilepsy, macrocephaly, and developmental delay, in line with the SYN1 LoF phenotype. Whether SYN1 autoantibodies have a direct pathogenic effect on neurodevelopment or serve as biomarkers requires functional experiments.

Keywords: antineuronal autoantibodies; behavioral problems; developmental delay; epilepsy; maternofetal autoimmunity; synapsin 1; transplacental transfer.

PubMed Disclaimer

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Phenotype of children of mothers tested for SYN1 autoantibodies. Developmental delay in the domains speech and motor skills were the most common findings, often associated with intellectual disability and epilepsy. ID, intellectual disability; ASD, autism-spectrum disorder.
Figure 2
Figure 2
Detection of synapsin 1 (SYN1) autoantibodies. (A) Examples of immunofluorescence stainings, using human sera at a 1:300 dilution (green) with or without binding to HEK cells overexpressing human SYN1b are shown in the top row and bottom row. Using a commercial SYN1/2 antibody, protein expression is verified (red). DAPI is used to stain the nuclei (blue). Scale bar: 20 µm. (B) In 9.6% of mothers SYN1 autoantibodies were detected using a CBA. (C) CBA and in-house ELISA correlated weakly, with higher mean serum IgG levels in the CBA-positive group. (D) Representative immunoblots of wild type (WT) and Syn1/2/3 triple KO (TKO) mice cortex homogenates with a commercial synapsin 1/2 antibody as positive control, and with sera (1:200 dilution) from a CBA-positive mother and a CBA-negative control. Major bands at 80-90 kDa corresponding to the molecular weight of synapsin 1a/1b and additional bands at 50-55 kDa that could represent the synapsin 2b isoform or breakdown products of synapsin 1 were detected in wild type but not in TKO mouse tissue by both the commercial antibody and the serum of the CBA-positive mother. Detection of GAPDH served as loading control. HEK human embryonic kidney; CBA, cell-based assay; ELISA, enzyme-linked immunosorbent assay, WB, western blot.
Figure 3
Figure 3
Clinical phenotype in patients of mothers with autoantibodies against synapsin 1 (SYN1). (A, B) Forest plot and bar chart showing the significantly increased risk for intellectual disability and behavioral problems. ID, intellectual disability; ASD, autism-spectrum disorder. * p ≤ 0.05.
See this image and copyright information in PMC

References

    1. Hilfiker S, Benfenati F, Doussau F, Nairn AC, Czernik AJ, Augustine GJ, et al. Structural domains involved in the regulation of transmitter release by synapsins. J Neurosci (2005) 25(10):2658–69. doi: 10.1523/jneurosci.4278-04.2005 - DOI - PMC - PubMed
    1. Valtorta F, Benfenati F, Greengard P. Structure and function of the synapsins. J Biol Chem (1992) 267(11):7195–8. doi: 10.1016/S0021-9258(18)42501-X - DOI - PubMed
    1. Garcia CC, Blair HJ, Seager M, Coulthard A, Tennant S, Buddles M, et al. Identification of a mutation in synapsin I, a synaptic vesicle protein, in a family with epilepsy. J Med Genet (2004) 41(3):183–6. doi: 10.1136/jmg.2003.013680 - DOI - PMC - PubMed
    1. Fassio A, Patry L, Congia S, Onofri F, Piton A, Gauthier J, et al. Syn1 loss-of-Function mutations in autism and partial epilepsy cause impaired synaptic function. Hum Mol Genet (2011) 20(12):2297–307. doi: 10.1093/hmg/ddr122 - DOI - PubMed
    1. Giannandrea M, Guarnieri FC, Gehring NH, Monzani E, Benfenati F, Kulozik AE, et al. Nonsense-mediated mrna decay and loss-of-Function of the protein underlie the X-linked epilepsy associated with the W356× mutation in synapsin I. PloS One (2013) 8(6):e67724. doi: 10.1371/journal.pone.0067724 - DOI - PMC - PubMed

Publication types