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LIN7A Depletion Disrupts Cerebral Cortex Development, Contributing to Intellectual Disability in 12q21-Deletion Syndrome
Interstitial deletion of 12q21 has been reported in four cases, which share several common clinical features, including intellectual disability (ID), low-set ears, and minor cardiac abnormalities. Comparative genomic hybridization (CGH) analysis using the Agilent Human Genome CGH 180K array was perf...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962435/ https://www.ncbi.nlm.nih.gov/pubmed/24658322 http://dx.doi.org/10.1371/journal.pone.0092695 |
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author | Matsumoto, Ayumi Mizuno, Makoto Hamada, Nanako Nozaki, Yasuyuki Jimbo, Eriko F. Momoi, Mariko Y. Nagata, Koh-ichi Yamagata, Takanori |
author_facet | Matsumoto, Ayumi Mizuno, Makoto Hamada, Nanako Nozaki, Yasuyuki Jimbo, Eriko F. Momoi, Mariko Y. Nagata, Koh-ichi Yamagata, Takanori |
author_sort | Matsumoto, Ayumi |
collection | PubMed |
description | Interstitial deletion of 12q21 has been reported in four cases, which share several common clinical features, including intellectual disability (ID), low-set ears, and minor cardiac abnormalities. Comparative genomic hybridization (CGH) analysis using the Agilent Human Genome CGH 180K array was performed with the genomic DNA from a two-year-old Japanese boy with these symptoms, as well as hypoplasia of the corpus callosum. Consequently, a 14 Mb deletion at 12q21.2-q21.33 (nt. 77 203 574–91 264 613 bp), which includes 72 genes, was detected. Of these, we focused on LIN7A, which encodes a scaffold protein that is important for synaptic function, as a possible responsible gene for ID, and we analyzed its role in cerebral cortex development. Western blotting analyses revealed that Lin-7A is expressed on embryonic day (E) 13.5, and gradually increases in the mouse brain during the embryonic stage. Biochemical fractionation resulted in the enrichment of Lin-7A in the presynaptic fraction. Suppression of Lin-7A expression by RNAi, using in utero electroporation on E14.5, delayed neuronal migration on postnatal day (P) 2, and Lin-7A-deficient neurons remained in the lower zone of the cortical plate and the intermediate zone. In addition, when Lin-7A was silenced in cortical neurons in one hemisphere, axonal growth in the contralateral hemisphere was delayed; development of these neurons was disrupted such that one half did not extend into the contralateral hemisphere after leaving the corpus callosum. Taken together, LIN7A is a candidate gene responsible for 12q21-deletion syndrome, and abnormal neuronal migration and interhemispheric axon development may contribute to ID and corpus callosum hypoplasia, respectively. |
format | Online Article Text |
id | pubmed-3962435 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-39624352014-03-24 LIN7A Depletion Disrupts Cerebral Cortex Development, Contributing to Intellectual Disability in 12q21-Deletion Syndrome Matsumoto, Ayumi Mizuno, Makoto Hamada, Nanako Nozaki, Yasuyuki Jimbo, Eriko F. Momoi, Mariko Y. Nagata, Koh-ichi Yamagata, Takanori PLoS One Research Article Interstitial deletion of 12q21 has been reported in four cases, which share several common clinical features, including intellectual disability (ID), low-set ears, and minor cardiac abnormalities. Comparative genomic hybridization (CGH) analysis using the Agilent Human Genome CGH 180K array was performed with the genomic DNA from a two-year-old Japanese boy with these symptoms, as well as hypoplasia of the corpus callosum. Consequently, a 14 Mb deletion at 12q21.2-q21.33 (nt. 77 203 574–91 264 613 bp), which includes 72 genes, was detected. Of these, we focused on LIN7A, which encodes a scaffold protein that is important for synaptic function, as a possible responsible gene for ID, and we analyzed its role in cerebral cortex development. Western blotting analyses revealed that Lin-7A is expressed on embryonic day (E) 13.5, and gradually increases in the mouse brain during the embryonic stage. Biochemical fractionation resulted in the enrichment of Lin-7A in the presynaptic fraction. Suppression of Lin-7A expression by RNAi, using in utero electroporation on E14.5, delayed neuronal migration on postnatal day (P) 2, and Lin-7A-deficient neurons remained in the lower zone of the cortical plate and the intermediate zone. In addition, when Lin-7A was silenced in cortical neurons in one hemisphere, axonal growth in the contralateral hemisphere was delayed; development of these neurons was disrupted such that one half did not extend into the contralateral hemisphere after leaving the corpus callosum. Taken together, LIN7A is a candidate gene responsible for 12q21-deletion syndrome, and abnormal neuronal migration and interhemispheric axon development may contribute to ID and corpus callosum hypoplasia, respectively. Public Library of Science 2014-03-21 /pmc/articles/PMC3962435/ /pubmed/24658322 http://dx.doi.org/10.1371/journal.pone.0092695 Text en © 2014 Matsumoto et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Matsumoto, Ayumi Mizuno, Makoto Hamada, Nanako Nozaki, Yasuyuki Jimbo, Eriko F. Momoi, Mariko Y. Nagata, Koh-ichi Yamagata, Takanori LIN7A Depletion Disrupts Cerebral Cortex Development, Contributing to Intellectual Disability in 12q21-Deletion Syndrome |
title | LIN7A Depletion Disrupts Cerebral Cortex Development, Contributing to Intellectual Disability in 12q21-Deletion Syndrome |
title_full | LIN7A Depletion Disrupts Cerebral Cortex Development, Contributing to Intellectual Disability in 12q21-Deletion Syndrome |
title_fullStr | LIN7A Depletion Disrupts Cerebral Cortex Development, Contributing to Intellectual Disability in 12q21-Deletion Syndrome |
title_full_unstemmed | LIN7A Depletion Disrupts Cerebral Cortex Development, Contributing to Intellectual Disability in 12q21-Deletion Syndrome |
title_short | LIN7A Depletion Disrupts Cerebral Cortex Development, Contributing to Intellectual Disability in 12q21-Deletion Syndrome |
title_sort | lin7a depletion disrupts cerebral cortex development, contributing to intellectual disability in 12q21-deletion syndrome |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3962435/ https://www.ncbi.nlm.nih.gov/pubmed/24658322 http://dx.doi.org/10.1371/journal.pone.0092695 |
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