A novel de novo GABRA2 gene missense variant causing developmental epileptic encephalopathy in a Chinese patient
Abstract Background Variants in the GABRA2 gene, which encodes the α2 subunit of the γ‐aminobutyric acid A receptor, have been linked to a rare form of developmental and epileptic encephalopathy (DEE) referred to as DEE78. Only eight patients have been reported globally. This study presents the clin...
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Wiley
2025-01-01
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| Series: | Annals of Clinical and Translational Neurology |
| Online Access: | https://doi.org/10.1002/acn3.52262 |
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| author | Li Yang Xingyu Wan Ran Hua Junhong Jiang Baotian Wang Rui Tao De Wu |
| author_facet | Li Yang Xingyu Wan Ran Hua Junhong Jiang Baotian Wang Rui Tao De Wu |
| author_sort | Li Yang |
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| description | Abstract Background Variants in the GABRA2 gene, which encodes the α2 subunit of the γ‐aminobutyric acid A receptor, have been linked to a rare form of developmental and epileptic encephalopathy (DEE) referred to as DEE78. Only eight patients have been reported globally. This study presents the clinical presentation and genetic analysis of a Chinese family with a child diagnosed with DEE78, due to a novel GABRA2 variant. Methods Genetic diagnosis was performed using trio‐whole exome sequencing, followed by bioinformatics predictions of pathogenicity. Structural modeling assessed the potential impact of the variant. A mutant plasmid was constructed and transfected into 293 T cells. Western blotting (WB) was used to evaluate mutant protein expression, while co‐immunoprecipitation (Co‐IP) analyzed interactions with GABRB3 and GABRG2 proteins. Immunofluorescence (IF) assessed the subcellular localization of the mutant protein. Results The 6‐year‐old male proband presented with seizures starting at age two, along with global developmental delay and hypotonia. Genetic testing revealed a heterozygous de novo variant in GABRA2 gene (NM_000807: c.923C>T, p.Ala308Val). Structural modeling suggested that this variant is located within the extracellular domain, which may disrupt hydrogen bonding interactions with GABRB3 and GABRG2. WB and Co‐IP showed reduced protein expression and impaired interactions, potentially destabilizing the pentamer receptor complex. If analysis revealed that the variant did not affect subcellular localization. Conclusion This study identified a novel likely pathogenic GABRA2 extracellular domain variant in a Chinese family causing the DEE phenotype. The results expand the genotypic and phenotypic spectrum of GABRA2‐related DEE. |
| format | Article |
| id | doaj-art-dbb3dc8575fa47449ea3b339fbd3cb2b |
| institution | Kabale University |
| issn | 2328-9503 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Annals of Clinical and Translational Neurology |
| spelling | doaj-art-dbb3dc8575fa47449ea3b339fbd3cb2b2025-01-21T05:41:42ZengWileyAnnals of Clinical and Translational Neurology2328-95032025-01-0112113714810.1002/acn3.52262A novel de novo GABRA2 gene missense variant causing developmental epileptic encephalopathy in a Chinese patientLi Yang0Xingyu Wan1Ran Hua2Junhong Jiang3Baotian Wang4Rui Tao5De Wu6Department of Pediatrics the First Affiliated Hospital of Anhui Medical University Hefei Anhui P. R. ChinaSecond School of Clinical Medicine Anhui Medical University Hefei Anhui P. R. ChinaDepartment of Pediatrics the First Affiliated Hospital of Anhui Medical University Hefei Anhui P. R. ChinaDepartment of Pediatrics the First Affiliated Hospital of Anhui Medical University Hefei Anhui P. R. ChinaDepartment of Pediatrics the First Affiliated Hospital of Anhui Medical University Hefei Anhui P. R. ChinaDepartment of Psychiatry Chaohu Hospital of Anhui Medical University Hefei ChinaDepartment of Pediatrics the First Affiliated Hospital of Anhui Medical University Hefei Anhui P. R. ChinaAbstract Background Variants in the GABRA2 gene, which encodes the α2 subunit of the γ‐aminobutyric acid A receptor, have been linked to a rare form of developmental and epileptic encephalopathy (DEE) referred to as DEE78. Only eight patients have been reported globally. This study presents the clinical presentation and genetic analysis of a Chinese family with a child diagnosed with DEE78, due to a novel GABRA2 variant. Methods Genetic diagnosis was performed using trio‐whole exome sequencing, followed by bioinformatics predictions of pathogenicity. Structural modeling assessed the potential impact of the variant. A mutant plasmid was constructed and transfected into 293 T cells. Western blotting (WB) was used to evaluate mutant protein expression, while co‐immunoprecipitation (Co‐IP) analyzed interactions with GABRB3 and GABRG2 proteins. Immunofluorescence (IF) assessed the subcellular localization of the mutant protein. Results The 6‐year‐old male proband presented with seizures starting at age two, along with global developmental delay and hypotonia. Genetic testing revealed a heterozygous de novo variant in GABRA2 gene (NM_000807: c.923C>T, p.Ala308Val). Structural modeling suggested that this variant is located within the extracellular domain, which may disrupt hydrogen bonding interactions with GABRB3 and GABRG2. WB and Co‐IP showed reduced protein expression and impaired interactions, potentially destabilizing the pentamer receptor complex. If analysis revealed that the variant did not affect subcellular localization. Conclusion This study identified a novel likely pathogenic GABRA2 extracellular domain variant in a Chinese family causing the DEE phenotype. The results expand the genotypic and phenotypic spectrum of GABRA2‐related DEE.https://doi.org/10.1002/acn3.52262 |
| spellingShingle | Li Yang Xingyu Wan Ran Hua Junhong Jiang Baotian Wang Rui Tao De Wu A novel de novo GABRA2 gene missense variant causing developmental epileptic encephalopathy in a Chinese patient Annals of Clinical and Translational Neurology |
| title | A novel de novo GABRA2 gene missense variant causing developmental epileptic encephalopathy in a Chinese patient |
| title_full | A novel de novo GABRA2 gene missense variant causing developmental epileptic encephalopathy in a Chinese patient |
| title_fullStr | A novel de novo GABRA2 gene missense variant causing developmental epileptic encephalopathy in a Chinese patient |
| title_full_unstemmed | A novel de novo GABRA2 gene missense variant causing developmental epileptic encephalopathy in a Chinese patient |
| title_short | A novel de novo GABRA2 gene missense variant causing developmental epileptic encephalopathy in a Chinese patient |
| title_sort | novel de novo gabra2 gene missense variant causing developmental epileptic encephalopathy in a chinese patient |
| url | https://doi.org/10.1002/acn3.52262 |
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