An unstable variant of GAP43 leads to neurodevelopmental deficiency
Abstract Growth-associated protein 43 (GAP43) is a membrane-associated phosphoprotein predominantly expressed in the nervous systems, and controls axonal growth, branching, and pathfinding. While the association between GAP43 and human neurological disorders have been reported, the underlying mechan...
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Nature Portfolio
2024-12-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-83445-w |
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| author | Mariko Noda Ayumi Matsumoto Hidenori Ito Masayo Kagami Toshihiro Tajima Takayoshi Matsumura Takanori Yamagata Koh-ichi Nagata |
| author_facet | Mariko Noda Ayumi Matsumoto Hidenori Ito Masayo Kagami Toshihiro Tajima Takayoshi Matsumura Takanori Yamagata Koh-ichi Nagata |
| author_sort | Mariko Noda |
| collection | DOAJ |
| description | Abstract Growth-associated protein 43 (GAP43) is a membrane-associated phosphoprotein predominantly expressed in the nervous systems, and controls axonal growth, branching, and pathfinding. While the association between GAP43 and human neurological disorders have been reported, the underlying mechanisms remain largely unknown. We performed whole exome sequencing on a patient with intellectual disability (ID), neurodevelopmental disorders, short stature, and skeletal abnormalities such as left–right difference in legs and digital deformities, and identified a heterozygous missense variation in the GAP43 gene [NM_001130064.2: c.436G > A/p.(E146K)]. The variant GAP43 protein was unstable in primary cultured cortical neurons and hippocampal neurons in vitro. In utero electroporation of the variant protein also confirmed its instability in vivo, suggesting that the variant led to a condition similar with haploinsufficiency in the patient. Silencing of GAP43 via in utero electroporation of RNAi vectors demonstrated that loss of GAP43 suppressed axon elongation into the contralateral hemisphere and impaired the dendritic arbor formation as shown by decreased dendritic branch points and shortened total dendritic lengths. Collectively, these findings confirmed the critical roles of GAP43 in brain development and the pathological basis of GAP43-associated diseases. Our study will contribute to a better understanding of how dysregulation of GAP43 leads to human diseases. |
| format | Article |
| id | doaj-art-c8c5c6f1e35b400e91a7af0c962b0dde |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-c8c5c6f1e35b400e91a7af0c962b0dde2025-01-05T12:30:11ZengNature PortfolioScientific Reports2045-23222024-12-0114111210.1038/s41598-024-83445-wAn unstable variant of GAP43 leads to neurodevelopmental deficiencyMariko Noda0Ayumi Matsumoto1Hidenori Ito2Masayo Kagami3Toshihiro Tajima4Takayoshi Matsumura5Takanori Yamagata6Koh-ichi Nagata7Department of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability CenterDepartment of Pediatrics, Jichi Medical UniversityDepartment of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability CenterClinical Endocrine Research Division, Department of Molecular Endocrinology, National Research Institute for Child Health and DevelopmentDepartment of Pediatrics, Jichi Medical UniversityDivision of Cardiovascular and Genetic Research, Center for Molecular Medicine, Jichi Medical UniversityDepartment of Pediatrics, Jichi Medical UniversityDepartment of Molecular Neurobiology, Institute for Developmental Research, Aichi Developmental Disability CenterAbstract Growth-associated protein 43 (GAP43) is a membrane-associated phosphoprotein predominantly expressed in the nervous systems, and controls axonal growth, branching, and pathfinding. While the association between GAP43 and human neurological disorders have been reported, the underlying mechanisms remain largely unknown. We performed whole exome sequencing on a patient with intellectual disability (ID), neurodevelopmental disorders, short stature, and skeletal abnormalities such as left–right difference in legs and digital deformities, and identified a heterozygous missense variation in the GAP43 gene [NM_001130064.2: c.436G > A/p.(E146K)]. The variant GAP43 protein was unstable in primary cultured cortical neurons and hippocampal neurons in vitro. In utero electroporation of the variant protein also confirmed its instability in vivo, suggesting that the variant led to a condition similar with haploinsufficiency in the patient. Silencing of GAP43 via in utero electroporation of RNAi vectors demonstrated that loss of GAP43 suppressed axon elongation into the contralateral hemisphere and impaired the dendritic arbor formation as shown by decreased dendritic branch points and shortened total dendritic lengths. Collectively, these findings confirmed the critical roles of GAP43 in brain development and the pathological basis of GAP43-associated diseases. Our study will contribute to a better understanding of how dysregulation of GAP43 leads to human diseases.https://doi.org/10.1038/s41598-024-83445-w |
| spellingShingle | Mariko Noda Ayumi Matsumoto Hidenori Ito Masayo Kagami Toshihiro Tajima Takayoshi Matsumura Takanori Yamagata Koh-ichi Nagata An unstable variant of GAP43 leads to neurodevelopmental deficiency Scientific Reports |
| title | An unstable variant of GAP43 leads to neurodevelopmental deficiency |
| title_full | An unstable variant of GAP43 leads to neurodevelopmental deficiency |
| title_fullStr | An unstable variant of GAP43 leads to neurodevelopmental deficiency |
| title_full_unstemmed | An unstable variant of GAP43 leads to neurodevelopmental deficiency |
| title_short | An unstable variant of GAP43 leads to neurodevelopmental deficiency |
| title_sort | unstable variant of gap43 leads to neurodevelopmental deficiency |
| url | https://doi.org/10.1038/s41598-024-83445-w |
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