Homozygous missense variants in NTNG2, encoding a presynaptic netrin-G2 adhesion protein, lead to a distinct neurodevelopmental disorder
NTNG2 encodes netrin-G2, a membrane-anchored protein implicated in the molecular organization of neuronal circuitry and synaptic organization and diversification in vertebrates. In this study, through a combination of exome sequencing and autozygosity mapping, we have identified 16 individuals (from...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Elsevier
2019
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| _version_ | 1826291041966227456 |
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| author | Dias, CM Punetha, J Zheng, C Mazaheri, N Rad, A Efthymiou, S Petersen, A Dehghani, M Pehlivan, D Partlow, JN Posey, JE Salpietro, V Gezdirici, A Malamiri, RA Menabawy, NM Selim, LA Mehrjardi, MY Banu, S Polla, DL Yang, E Varaghchi, J Mitani, T Van Beusekom, E Najafi, M Sedaghat, A Keller-Ramey, J Durham, L Coban-Akdemir, Z Karaca, E Orlova, V Schaeken, LLM Sherafat, A Jhangiani, SN Stanley, V Shariati, G Galehdari, H Gleeson, JG Walsh, CA Lupski, JR Seiradake, E Houlden, H Van Bokhoven, H Maroofian, R |
| author_facet | Dias, CM Punetha, J Zheng, C Mazaheri, N Rad, A Efthymiou, S Petersen, A Dehghani, M Pehlivan, D Partlow, JN Posey, JE Salpietro, V Gezdirici, A Malamiri, RA Menabawy, NM Selim, LA Mehrjardi, MY Banu, S Polla, DL Yang, E Varaghchi, J Mitani, T Van Beusekom, E Najafi, M Sedaghat, A Keller-Ramey, J Durham, L Coban-Akdemir, Z Karaca, E Orlova, V Schaeken, LLM Sherafat, A Jhangiani, SN Stanley, V Shariati, G Galehdari, H Gleeson, JG Walsh, CA Lupski, JR Seiradake, E Houlden, H Van Bokhoven, H Maroofian, R |
| author_sort | Dias, CM |
| collection | OXFORD |
| description | NTNG2 encodes netrin-G2, a membrane-anchored protein implicated in the molecular organization of neuronal circuitry and synaptic organization and diversification in vertebrates. In this study, through a combination of exome sequencing and autozygosity mapping, we have identified 16 individuals (from seven unrelated families) with ultra-rare homozygous missense variants in NTNG2; these individuals present with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features, behavioral abnormalities, and variable dysmorphisms. The variants disrupt highly conserved residues across the protein. Functional experiments, including in silico analysis of the protein structure, in vitro assessment of cell surface expression, and in vitro knockdown, revealed potential mechanisms of pathogenicity of the variants, including loss of protein function and decreased neurite outgrowth. Our data indicate that appropriate expression of NTNG2 plays an important role in neurotypical development. |
| first_indexed | 2024-03-07T02:53:26Z |
| format | Journal article |
| id | oxford-uuid:ae7999bb-b634-4ab9-a5b8-c0674b5110c6 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T02:53:26Z |
| publishDate | 2019 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:ae7999bb-b634-4ab9-a5b8-c0674b5110c62022-03-27T03:43:01ZHomozygous missense variants in NTNG2, encoding a presynaptic netrin-G2 adhesion protein, lead to a distinct neurodevelopmental disorderJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:ae7999bb-b634-4ab9-a5b8-c0674b5110c6EnglishSymplectic Elements at OxfordElsevier2019Dias, CMPunetha, JZheng, CMazaheri, NRad, AEfthymiou, SPetersen, ADehghani, MPehlivan, DPartlow, JNPosey, JESalpietro, VGezdirici, AMalamiri, RAMenabawy, NMSelim, LAMehrjardi, MYBanu, SPolla, DLYang, EVaraghchi, JMitani, TVan Beusekom, ENajafi, MSedaghat, AKeller-Ramey, JDurham, LCoban-Akdemir, ZKaraca, EOrlova, VSchaeken, LLMSherafat, AJhangiani, SNStanley, VShariati, GGalehdari, HGleeson, JGWalsh, CALupski, JRSeiradake, EHoulden, HVan Bokhoven, HMaroofian, RNTNG2 encodes netrin-G2, a membrane-anchored protein implicated in the molecular organization of neuronal circuitry and synaptic organization and diversification in vertebrates. In this study, through a combination of exome sequencing and autozygosity mapping, we have identified 16 individuals (from seven unrelated families) with ultra-rare homozygous missense variants in NTNG2; these individuals present with shared features of a neurodevelopmental disorder consisting of global developmental delay, severe to profound intellectual disability, muscle weakness and abnormal tone, autistic features, behavioral abnormalities, and variable dysmorphisms. The variants disrupt highly conserved residues across the protein. Functional experiments, including in silico analysis of the protein structure, in vitro assessment of cell surface expression, and in vitro knockdown, revealed potential mechanisms of pathogenicity of the variants, including loss of protein function and decreased neurite outgrowth. Our data indicate that appropriate expression of NTNG2 plays an important role in neurotypical development. |
| spellingShingle | Dias, CM Punetha, J Zheng, C Mazaheri, N Rad, A Efthymiou, S Petersen, A Dehghani, M Pehlivan, D Partlow, JN Posey, JE Salpietro, V Gezdirici, A Malamiri, RA Menabawy, NM Selim, LA Mehrjardi, MY Banu, S Polla, DL Yang, E Varaghchi, J Mitani, T Van Beusekom, E Najafi, M Sedaghat, A Keller-Ramey, J Durham, L Coban-Akdemir, Z Karaca, E Orlova, V Schaeken, LLM Sherafat, A Jhangiani, SN Stanley, V Shariati, G Galehdari, H Gleeson, JG Walsh, CA Lupski, JR Seiradake, E Houlden, H Van Bokhoven, H Maroofian, R Homozygous missense variants in NTNG2, encoding a presynaptic netrin-G2 adhesion protein, lead to a distinct neurodevelopmental disorder |
| title | Homozygous missense variants in NTNG2, encoding a presynaptic netrin-G2 adhesion protein, lead to a distinct neurodevelopmental disorder |
| title_full | Homozygous missense variants in NTNG2, encoding a presynaptic netrin-G2 adhesion protein, lead to a distinct neurodevelopmental disorder |
| title_fullStr | Homozygous missense variants in NTNG2, encoding a presynaptic netrin-G2 adhesion protein, lead to a distinct neurodevelopmental disorder |
| title_full_unstemmed | Homozygous missense variants in NTNG2, encoding a presynaptic netrin-G2 adhesion protein, lead to a distinct neurodevelopmental disorder |
| title_short | Homozygous missense variants in NTNG2, encoding a presynaptic netrin-G2 adhesion protein, lead to a distinct neurodevelopmental disorder |
| title_sort | homozygous missense variants in ntng2 encoding a presynaptic netrin g2 adhesion protein lead to a distinct neurodevelopmental disorder |
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