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: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Journal article |
| Language: | English |
| Published: |
Elsevier
2019
|
| _version_ | 1797088674622472192 |
|---|---|
| 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 |
| work_keys_str_mv | AT diascm homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT punethaj homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT zhengc homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT mazaherin homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT rada homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT efthymious homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT petersena homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT dehghanim homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT pehlivand homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT partlowjn homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT poseyje homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT salpietrov homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT gezdiricia homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT malamirira homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT menabawynm homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT selimla homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT mehrjardimy homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT banus homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT polladl homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT yange homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT varaghchij homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT mitanit homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT vanbeusekome homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT najafim homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT sedaghata homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT kellerrameyj homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT durhaml homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT cobanakdemirz homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT karacae homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT orlovav homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT schaekenllm homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT sherafata homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT jhangianisn homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT stanleyv homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT shariatig homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT galehdarih homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT gleesonjg homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT walshca homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT lupskijr homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT seiradakee homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT houldenh homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT vanbokhovenh homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder AT maroofianr homozygousmissensevariantsinntng2encodingapresynapticnetring2adhesionproteinleadtoadistinctneurodevelopmentaldisorder |