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Homozygous frameshift variant in NTNG2, encoding a synaptic cell adhesion molecule, in individuals with developmental delay, hypotonia, and autistic features

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Abstract

Regulation of neuronal connectivity and synaptic communication are key to proper functioning of the brain. The Netrin-G subfamily and their cognate receptors are vertebrate-specific synaptic cell adhesion molecules with a role in synapse establishment and function, which seem to have co-evolved to contribute to higher brain functions. We identified a homozygous frameshift variant in NTNG2 (NM_032536.3: c.376dup), encoding Netrin-G2, in eight individuals from four families with global developmental delay, hypotonia, secondary microcephaly, and autistic features. Comparison of haplotypes established this as a founder variant. Previous studies showed that Ntng2-knockout mice have impaired visual, auditory, and motor coordination abilities required for demanding tasks, as well as possible spatial learning and memory deficits. Knockout of Ntng2 in a cellular model resulted in short neurites, and knockout of its trans-synaptic partner Ngl2/Lrrc4 in mice revealed autistic-like behavior and reduced NMDAR synaptic plasticity. The Ngl2/Lrrc4-knockout mouse phenotype was rescued by NMDAR activation, suggesting a mechanistic link to autism spectrum disorder. We thus propose NTNG2 as a candidate disease gene and provide further support for the involvement of Netrin-G2 in neuropsychiatric phenotypes.

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References

  1. Soto F, Watkins KL, Johnson RE, Schottler F, Kerschensteiner D (2013) NGL-2 regulates pathway-specific neurite growth and lamination, synapse formation, and signal transmission in the retina. J Neurosci 33:11949–11959

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Matsukawa H, Akiyoshi-Nishimura S, Zhang Q, Lujan R, Yamaguchi K, Goto H, Yaguchi K, Hashikawa T, Sano C, Shigemoto R, Nakashiba T, Itohara S (2014) Netrin-G/NGL complexes encode functional synaptic diversification. J Neurosci 34:15779–15792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Um SM, Ha S, Lee H, Kim J, Kim K, Shin W, Cho YS, Roh JD, Kang J, Yoo T, Noh YW, Choi Y, Bae YC, Kim E (2018) NGL-2 deletion leads to autistic-like behaviors responsive to NMDAR modulation. Cell Rep 23:3839–3851

    Article  CAS  PubMed  Google Scholar 

  4. Bourgeron T (2015) From the genetic architecture to synaptic plasticity in autism spectrum disorder. Nat Rev Neurosci 16:551–563

    Article  CAS  PubMed  Google Scholar 

  5. de Wit J, Ghosh A (2014) Control of neural circuit formation by leucine-rich repeat proteins. Trends Neurosci 37:539–550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jang S, Lee H, Kim E (2017) Synaptic adhesion molecules and excitatory synaptic transmission. Curr Opin Neurobiol 45:45–50

    Article  CAS  PubMed  Google Scholar 

  7. Lai Wing Sun K, Correia JP, Kennedy TE (2011) Netrins: versatile extracellular cues with diverse functions. Development 138:2153–2169

    Article  CAS  PubMed  Google Scholar 

  8. Nishimura-Akiyoshi S, Niimi K, Nakashiba T, Itohara S (2007) Axonal netrin-Gs transneuronally determine lamina-specific subdendritic segments. Proc Natl Acad Sci U S A 104:14801–14806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Nakashiba T, Nishimura S, Ikeda T, Itohara S (2002) Complementary expression and neurite outgrowth activity of netrin-G subfamily members. Mech Dev 111:47–60

    Article  CAS  PubMed  Google Scholar 

  10. Yin Y, Miner JH, Sanes JR (2002) Laminets: laminin- and netrin-related genes expressed in distinct neuronal subsets. Mol Cell Neurosci 19:344–358

    Article  CAS  PubMed  Google Scholar 

  11. Seiradake E, Coles CH, Perestenko PV, Harlos K, McIlhinney RAJ, Aricescu AR, Jones EY (2011) Structural basis for cell surface patterning through NetrinG-NGL interactions. EMBO J 30:4479–4488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Zhang Q, Goto H, Akiyoshi-Nishimura S, Prosselkov P, Sano C, Matsukawa H, Yaguchi K, Nakashiba T, Itohara S (2016) Diversification of behavior and postsynaptic properties by netrin-G presynaptic adhesion family proteins. Mol Brain 9:6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Woo J, Kwon SK, Kim E (2009) The NGL family of leucine-rich repeat-containing synaptic adhesion molecules. Mol Cell Neurosci 42:1–10

    Article  CAS  PubMed  Google Scholar 

  14. Xu G, Wang R, Wang Z, Lei Q, Yu Z, Liu C, Li P, Yang Z, Cheng X, Li G, Wu M (2015) NGL-2 is a new partner of PAR complex in axon differentiation. J Neurosci 35:7153–7164

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Aoki-Suzuki M, Yamada K, Meerabux J, Iwayama-Shigeno Y, Ohba H, Iwamoto K, Takao H, Toyota T, Suto Y, Nakatani N, Dean B, Nishimura S, Seki K, Kato T, Itohara S, Nishikawa T, Yoshikawa T (2005) A family-based association study and gene expression analyses of netrin-G1 and -G2 genes in schizophrenia. Biol Psychiatry 57:382–393

    Article  CAS  PubMed  Google Scholar 

  16. Ohtsuki T, Horiuchi Y, Koga M, Ishiguro H, Inada T, Iwata N, Ozaki N, Ujike H, Watanabe Y, Someya T, Arinami T (2008) Association of polymorphisms in the haplotype block spanning the alternatively spliced exons of the NTNG1 gene at 1p13.3 with schizophrenia in Japanese populations. Neurosci Lett 435:194–197

    Article  CAS  PubMed  Google Scholar 

  17. Eastwood SL, Harrison PJ (2008) Decreased mRNA expression of netrin-G1 and netrin-G2 in the temporal lobe in schizophrenia and bipolar disorder. Neuropsychopharmacology 33:933–945

    Article  CAS  PubMed  Google Scholar 

  18. Sangu N, Shimojima K, Takahashi Y, Ohashi T, Tohyama J, Yamamoto T (2017) A 7q31.33q32.1 microdeletion including. Hum Genome Var 4:17001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Borg I, Freude K, Kübart S, Hoffmann K, Menzel C, Laccone F, Firth H, Ferguson-Smith MA, Tommerup N, Ropers HH, Sargan D, Kalscheuer VM (2005) Disruption of Netrin G1 by a balanced chromosome translocation in a girl with Rett syndrome. Eur J Hum Genet 13:921–927

    Article  CAS  PubMed  Google Scholar 

  20. Ricciardi S, Ungaro F, Hambrock M, Rademacher N, Stefanelli G, Brambilla D, Sessa A, Magagnotti C, Bachi A, Giarda E, Verpelli C, Kilstrup-Nielsen C, Sala C, Kalscheuer VM, Broccoli V (2012) CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons. Nat Cell Biol 14:911–923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wei G, Deng X, Agarwal S, Iwase S, Disteche C, Xu J (2016) Patient mutations of the intellectual disability gene KDM5C downregulate netrin G2 and suppress neurite growth in Neuro2a cells. J Mol Neurosci 60:33–45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors wish to thank the families for their participation in this study.

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Author notes

  1. Bassam Abu-Libdeh and Motee Ashhab contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatrics, Makassed Hospital and Al-Quds University, East Jerusalem, Palestine

    Bassam Abu-Libdeh, Motee Ashhab & Maher Shahrour

  2. Child Development Centers, Clalit and Maccabi Health Care Services, Jerusalem, Israel

    Muhannad Daana

  3. Consultant Pediatric Neurologist, Takween Center, Ramallah, Palestine

    Anwar Dudin

  4. Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel

    Orly Elpeleg & Simon Edvardson

  5. Pediatric Neurology Unit, Hadassah-Hebrew University Medical Center, 9112001, Jerusalem, Israel

    Simon Edvardson

  6. Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, POB 12000, 9112001, Jerusalem, Israel

    Tamar Harel

Authors
  1. Bassam Abu-Libdeh
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  2. Motee Ashhab
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Correspondence to Tamar Harel.

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Abu-Libdeh, B., Ashhab, M., Shahrour, M. et al. Homozygous frameshift variant in NTNG2, encoding a synaptic cell adhesion molecule, in individuals with developmental delay, hypotonia, and autistic features. Neurogenetics 20, 209–213 (2019). https://doi.org/10.1007/s10048-019-00583-4

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  • DOI: https://doi.org/10.1007/s10048-019-00583-4

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