Homozygous frameshift variant in NTNG2, encoding a synaptic cell adhesion molecule, in individuals with developmental delay, hypotonia, and autistic features
| Autor: | Bassam Abu-Libdeh, Simon Edvardson, Tamar Harel, Orly Elpeleg, Muhannad Daana, Anwar Dudin, Maher Shahrour, Motee Ashhab |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Developmental Disabilities Biology GPI-Linked Proteins Frameshift mutation Synapse 03 medical and health sciences Cellular and Molecular Neuroscience 0302 clinical medicine Cell Adhesion Genetics medicine Humans Exome Global developmental delay Autistic Disorder Child Frameshift Mutation Genetics (clinical) Neuronal Plasticity Homozygote medicine.disease Phenotype Hypotonia Pedigree Motor coordination 030104 developmental biology Haplotypes Autism spectrum disorder Synapses Synaptic plasticity Muscle Hypotonia Female Netrins medicine.symptom Cell Adhesion Molecules Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | neurogenetics. 20:209-213 |
| ISSN: | 1364-6753 1364-6745 |
| DOI: | 10.1007/s10048-019-00583-4 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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