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Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy
OBJECTIVE: The LAMA5 gene encodes the laminin subunit α5, the most abundant laminin α subunit in the human brain. It forms heterotrimers with the subunit β1/β2 and γ1/γ3 and regulates neurodevelopmental processes. Genes encoding subunits of the laminin heterotrimers containing subunit α5 have been r...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9162154/ https://www.ncbi.nlm.nih.gov/pubmed/35663266 http://dx.doi.org/10.3389/fnmol.2022.825390 |
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author | Luo, Sheng Liu, Zhi-Gang Wang, Juan Luo, Jun-Xia Ye, Xing-Guang Li, Xin Zhai, Qiong-Xiang Liu, Xiao-Rong Wang, Jie Gao, Liang-Di Liu, Fu-Li Ye, Zi-Long Li, Huan Gao, Zai-Fen Guo, Qing-Hui Li, Bing-Mei Yi, Yong-Hong Liao, Wei-Ping |
author_facet | Luo, Sheng Liu, Zhi-Gang Wang, Juan Luo, Jun-Xia Ye, Xing-Guang Li, Xin Zhai, Qiong-Xiang Liu, Xiao-Rong Wang, Jie Gao, Liang-Di Liu, Fu-Li Ye, Zi-Long Li, Huan Gao, Zai-Fen Guo, Qing-Hui Li, Bing-Mei Yi, Yong-Hong Liao, Wei-Ping |
author_sort | Luo, Sheng |
collection | PubMed |
description | OBJECTIVE: The LAMA5 gene encodes the laminin subunit α5, the most abundant laminin α subunit in the human brain. It forms heterotrimers with the subunit β1/β2 and γ1/γ3 and regulates neurodevelopmental processes. Genes encoding subunits of the laminin heterotrimers containing subunit α5 have been reported to be associated with human diseases. Among LAMAs encoding the laminin α subunit, LAMA1-4 have also been reported to be associated with human disease. In this study, we investigated the association between LAMA5 and epilepsy. METHODS: Trios-based whole-exome sequencing was performed in a cohort of 118 infants suffering from focal seizures with or without spasms. Protein modeling was used to assess the damaging effects of variations. The LAMAs expression was analyzed with data from the GTEX and VarCards databases. RESULTS: Six pairs of compound heterozygous missense variants in LAMA5 were identified in six unrelated patients. All affected individuals suffered from focal seizures with mild developmental delay, and three patients presented also spasms. These variants had no or low allele frequencies in controls and presented statistically higher frequency in the case cohort than in controls. The recessive burden analysis showed that recessive LAMA5 variants identified in this cohort were significantly more than the expected number in the East Asian population. Protein modeling showed that at least one variant in each pair of biallelic variants affected hydrogen bonds with surrounding amino acids. Among the biallelic variants in cases with only focal seizures, two variants of each pair were located in different structural domains or domains/links, whereas in the cases with spasms, the biallelic variants were constituted by two variants in the identical functional domains or both with hydrogen bond changes. CONCLUSION: Recessive LAMA5 variants were potentially associated with infant epilepsy. The establishment of the association between LAMA5 and epilepsy will facilitate the genetic diagnosis and management in patients with infant epilepsy. |
format | Online Article Text |
id | pubmed-9162154 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-91621542022-06-03 Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy Luo, Sheng Liu, Zhi-Gang Wang, Juan Luo, Jun-Xia Ye, Xing-Guang Li, Xin Zhai, Qiong-Xiang Liu, Xiao-Rong Wang, Jie Gao, Liang-Di Liu, Fu-Li Ye, Zi-Long Li, Huan Gao, Zai-Fen Guo, Qing-Hui Li, Bing-Mei Yi, Yong-Hong Liao, Wei-Ping Front Mol Neurosci Neuroscience OBJECTIVE: The LAMA5 gene encodes the laminin subunit α5, the most abundant laminin α subunit in the human brain. It forms heterotrimers with the subunit β1/β2 and γ1/γ3 and regulates neurodevelopmental processes. Genes encoding subunits of the laminin heterotrimers containing subunit α5 have been reported to be associated with human diseases. Among LAMAs encoding the laminin α subunit, LAMA1-4 have also been reported to be associated with human disease. In this study, we investigated the association between LAMA5 and epilepsy. METHODS: Trios-based whole-exome sequencing was performed in a cohort of 118 infants suffering from focal seizures with or without spasms. Protein modeling was used to assess the damaging effects of variations. The LAMAs expression was analyzed with data from the GTEX and VarCards databases. RESULTS: Six pairs of compound heterozygous missense variants in LAMA5 were identified in six unrelated patients. All affected individuals suffered from focal seizures with mild developmental delay, and three patients presented also spasms. These variants had no or low allele frequencies in controls and presented statistically higher frequency in the case cohort than in controls. The recessive burden analysis showed that recessive LAMA5 variants identified in this cohort were significantly more than the expected number in the East Asian population. Protein modeling showed that at least one variant in each pair of biallelic variants affected hydrogen bonds with surrounding amino acids. Among the biallelic variants in cases with only focal seizures, two variants of each pair were located in different structural domains or domains/links, whereas in the cases with spasms, the biallelic variants were constituted by two variants in the identical functional domains or both with hydrogen bond changes. CONCLUSION: Recessive LAMA5 variants were potentially associated with infant epilepsy. The establishment of the association between LAMA5 and epilepsy will facilitate the genetic diagnosis and management in patients with infant epilepsy. Frontiers Media S.A. 2022-05-19 /pmc/articles/PMC9162154/ /pubmed/35663266 http://dx.doi.org/10.3389/fnmol.2022.825390 Text en Copyright © 2022 Luo, Liu, Wang, Luo, Ye, Li, Zhai, Liu, Wang, Gao, Liu, Ye, Li, Gao, Guo, Li, Yi and Liao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Neuroscience Luo, Sheng Liu, Zhi-Gang Wang, Juan Luo, Jun-Xia Ye, Xing-Guang Li, Xin Zhai, Qiong-Xiang Liu, Xiao-Rong Wang, Jie Gao, Liang-Di Liu, Fu-Li Ye, Zi-Long Li, Huan Gao, Zai-Fen Guo, Qing-Hui Li, Bing-Mei Yi, Yong-Hong Liao, Wei-Ping Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy |
title | Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy |
title_full | Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy |
title_fullStr | Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy |
title_full_unstemmed | Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy |
title_short | Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy |
title_sort | recessive lama5 variants associated with partial epilepsy and spasms in infancy |
topic | Neuroscience |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9162154/ https://www.ncbi.nlm.nih.gov/pubmed/35663266 http://dx.doi.org/10.3389/fnmol.2022.825390 |
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