Neuropathology of 16p13.11 Deletion in Epilepsy
Publication Date
April 16, 2012
Journal
PLOS ONE
Authors
Joan Y. W. Liu, Dalia Kasperavičiūtė, Lillian Martinian, Maria Thom, et al
Volume
7
Issue
4
Pages
e34813
DOI
https://dx.plos.org/10.1371/journal.pone.0034813
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0034813
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/22523559
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3327721
Europe PMC
http://europepmc.org/abstract/MED/22523559
Web of Science
000305345000031
Scopus
84859809937
Mendeley
http://www.mendeley.com/research/neuropathology-16p1311-deletion-epilepsy
Events
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Mendeley | Further Information

{"title"=>"Neuropathology of 16p13.11 deletion in epilepsy", "type"=>"journal", "authors"=>[{"first_name"=>"Joan Y W", "last_name"=>"Liu", "scopus_author_id"=>"36056919800"}, {"first_name"=>"Dalia", "last_name"=>"Kasperavičiute", "scopus_author_id"=>"55890978500"}, {"first_name"=>"Lillian", "last_name"=>"Martinian", "scopus_author_id"=>"6603131683"}, {"first_name"=>"Maria", "last_name"=>"Thom", "scopus_author_id"=>"7004423623"}, {"first_name"=>"Sanjay M.", "last_name"=>"Sisodiya", "scopus_author_id"=>"7005111176"}], "year"=>2012, "source"=>"PLoS ONE", "identifiers"=>{"isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"22523559", "doi"=>"10.1371/journal.pone.0034813", "pui"=>"364638366", "issn"=>"19326203", "sgr"=>"84859809937", "scopus"=>"2-s2.0-84859809937"}, "id"=>"91e086f0-21aa-346e-9f5e-9f0932b040bb", "abstract"=>"16p13.11 genomic copy number variants are implicated in several neuropsychiatric disorders, such as schizophrenia, autism, mental retardation, ADHD and epilepsy. The mechanisms leading to the diverse clinical manifestations of deletions and duplications at this locus are unknown. Most studies favour NDE1 as the leading disease-causing candidate gene at 16p13.11. In epilepsy at least, the deletion does not appear to unmask recessive-acting mutations in NDE1, with haploinsufficiency and genetic modifiers being prime candidate disease mechanisms. NDE1 encodes a protein critical to cell positioning during cortical development. As a first step, it is important to determine whether 16p13.11 copy number change translates to detectable brain structural alteration. We undertook detailed neuropathology on surgically resected brain tissue of two patients with intractable mesial temporal lobe epilepsy (MTLE), who had the same heterozygous NDE1-containing 800 kb 16p13.11 deletion, using routine histological stains and immunohistochemical markers against a range of layer-specific, white matter, neural precursor and migratory cell proteins, and NDE1 itself. Surgical temporal lobectomy samples from a MTLE case known not to have a deletion in NDE1 and three non-epilepsy cases were included as disease controls. We found that apart from a 3 mm hamartia in the temporal cortex of one MTLE case with NDE1 deletion and known hippocampal sclerosis in the other case, cortical lamination and cytoarchitecture were normal, with no differences between cases with deletion and disease controls. How 16p13.11 copy changes lead to a variety of brain diseases remains unclear, but at least in epilepsy, it would not seem to be through structural abnormality or dyslamination as judged by microscopy or immunohistochemistry. The need to integrate additional data with genetic findings to determine their significance will become more pressing as genetic technologies generate increasingly rich datasets. Detailed examination of brain tissue, where available, will be an important part of this process in neurogenetic disease specifically.", "link"=>"http://www.mendeley.com/research/neuropathology-16p1311-deletion-epilepsy", "reader_count"=>38, "reader_count_by_academic_status"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Researcher"=>8, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>1, "Student > Master"=>5, "Other"=>5, "Student > Bachelor"=>3, "Lecturer"=>1, "Professor"=>6}, "reader_count_by_user_role"=>{"Unspecified"=>2, "Professor > Associate Professor"=>1, "Researcher"=>8, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>1, "Student > Master"=>5, "Other"=>5, "Student > Bachelor"=>3, "Lecturer"=>1, "Professor"=>6}, "reader_count_by_subject_area"=>{"Unspecified"=>3, "Biochemistry, Genetics and Molecular Biology"=>1, "Medicine and Dentistry"=>16, "Agricultural and Biological Sciences"=>9, "Neuroscience"=>3, "Psychology"=>3, "Computer Science"=>2, "Decision Sciences"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>16}, "Neuroscience"=>{"Neuroscience"=>3}, "Decision Sciences"=>{"Decision Sciences"=>1}, "Psychology"=>{"Psychology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>9}, "Computer Science"=>{"Computer Science"=>2}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Unspecified"=>{"Unspecified"=>3}}, "reader_count_by_country"=>{"Italy"=>1, "Portugal"=>1, "Iceland"=>1}, "group_count"=>1}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/652764"], "description"=>"<p>(A) A coronal MRI image of Case 2 showing left hippocampal atrophy (*; inset). No cerebral malformations were evident. The histology showed hippocampal sclerosis: (B) NeuN-immunopositive cells were lost in the cornu Ammonis (CA) regions of the left hippocampus of Case 2, as seen in the MTLE control case without <i>NDE1</i> deletion (C). (D) Strong GFAP-immunoreactivity was observed in all regions of the hippocampus of Case 2. (E) Dynorphin-immunoreactivity was observed throughout the molecular layer of Case 2, demonstrating the presence of mossy fibre spouting. GCL = granule cell layer, MOL = molecular cell layer. Scale = 100 µm (B–E).</p>", "links"=>[], "tags"=>["sclerosis"], "article_id"=>323257, "categories"=>["Biological Sciences", "Cell Biology", "Genetics"], "users"=>["Joan Y. W. Liu", "Dalia Kasperavičiūtė", "Lillian Martinian", "Maria Thom", "Sanjay M. Sisodiya"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034813.g003", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hippocampal_sclerosis_in_Case_2_/323257", "title"=>"Hippocampal sclerosis in Case 2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-16 00:54:17"}
  • {"files"=>["https://ndownloader.figshare.com/files/654071"], "description"=>"<p>mw = microwave; RT = room temperature.</p>", "links"=>[], "tags"=>["antibodies"], "article_id"=>324569, "categories"=>["Biological Sciences", "Cell Biology", "Genetics"], "users"=>["Joan Y. W. Liu", "Dalia Kasperavičiūtė", "Lillian Martinian", "Maria Thom", "Sanjay M. Sisodiya"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034813.t002", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Primary_antibodies_used_in_the_study_/324569", "title"=>"Primary antibodies used in the study.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-04-16 01:16:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/653731"], "description"=>"<p>The immunoreactivity of NDE1 (arrows) was predominantly observed in the cytoplasm of neurons in Case 2 and the epilepsy control.</p>", "links"=>[], "tags"=>["labelling", "temporal", "cortex", "mtle"], "article_id"=>324219, "categories"=>["Biological Sciences", "Cell Biology", "Genetics"], "users"=>["Joan Y. W. Liu", "Dalia Kasperavičiūtė", "Lillian Martinian", "Maria Thom", "Sanjay M. Sisodiya"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034813.g008", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_NDE1_immunopositive_labelling_in_the_temporal_cortex_of_Case_2_and_MTLE_case_without_NDE1_deletion_/324219", "title"=>"NDE1-immunopositive labelling in the temporal cortex of Case 2 and MTLE case without <i>NDE1</i> deletion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-16 01:10:19"}
  • {"files"=>["https://ndownloader.figshare.com/files/653332"], "description"=>"<p>Nestin- (A) and GFAPδ (B) strongly immunopositive glial-like cells were observed in cortical layer I and white matter of the temporal cortex and the hippocampus of Case 2. Nestin-immunopositive cells with short, unipolar processes were occasionally found in the white matter of Case 2 (A, middle inset). Small, round PAX6-immunopositive cells were found throughout the temporal cortex and hippocampus. BV = blood vessels, CA = cornu Ammonis, GCL = granule cell layer. Scale = 20 µm (A–C), 10 µm (A, middle inset).</p>", "links"=>[], "tags"=>["pax6", "immunopositive", "labelling", "temporal", "cortex", "hippocampus"], "article_id"=>323820, "categories"=>["Biological Sciences", "Cell Biology", "Genetics"], "users"=>["Joan Y. W. Liu", "Dalia Kasperavičiūtė", "Lillian Martinian", "Maria Thom", "Sanjay M. Sisodiya"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034813.g006", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Nestin_GFAP_948_and_PAX6_immunopositive_labelling_in_the_temporal_cortex_and_hippocampus_of_Case_2_/323820", "title"=>"Nestin, GFAPδ and PAX6 immunopositive labelling in the temporal cortex and hippocampus of Case 2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-16 01:03:40"}
  • {"files"=>["https://ndownloader.figshare.com/files/335329", "https://ndownloader.figshare.com/files/335413"], "description"=>"<div><p>16p13.11 genomic copy number variants are implicated in several neuropsychiatric disorders, such as schizophrenia, autism, mental retardation, ADHD and epilepsy. The mechanisms leading to the diverse clinical manifestations of deletions and duplications at this locus are unknown. Most studies favour <em>NDE1</em> as the leading disease-causing candidate gene at 16p13.11. In epilepsy at least, the deletion does not appear to unmask recessive-acting mutations in <em>NDE1</em>, with haploinsufficiency and genetic modifiers being prime candidate disease mechanisms. <em>NDE1</em> encodes a protein critical to cell positioning during cortical development. As a first step, it is important to determine whether 16p13.11 copy number change translates to detectable brain structural alteration. We undertook detailed neuropathology on surgically resected brain tissue of two patients with intractable mesial temporal lobe epilepsy (MTLE), who had the same heterozygous <em>NDE1</em>-containing 800 kb 16p13.11 deletion, using routine histological stains and immunohistochemical markers against a range of layer-specific, white matter, neural precursor and migratory cell proteins, and NDE1 itself. Surgical temporal lobectomy samples from a MTLE case known not to have a deletion in <em>NDE1</em> and three non-epilepsy cases were included as disease controls. We found that apart from a 3 mm hamartia in the temporal cortex of one MTLE case with <em>NDE1</em> deletion and known hippocampal sclerosis in the other case, cortical lamination and cytoarchitecture were normal, with no differences between cases with deletion and disease controls. How 16p13.11 copy changes lead to a variety of brain diseases remains unclear, but at least in epilepsy, it would not seem to be through structural abnormality or dyslamination as judged by microscopy or immunohistochemistry. The need to integrate additional data with genetic findings to determine their significance will become more pressing as genetic technologies generate increasingly rich datasets. Detailed examination of brain tissue, where available, will be an important part of this process in neurogenetic disease specifically.</p> </div>", "links"=>[], "tags"=>["neuropathology", "deletion", "epilepsy"], "article_id"=>126249, "categories"=>["Biological Sciences", "Cell Biology", "Genetics"], "users"=>["Joan Y. W. Liu", "Dalia Kasperavičiūtė", "Lillian Martinian", "Maria Thom", "Sanjay M. Sisodiya"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0034813.s001", "https://dx.doi.org/10.1371/journal.pone.0034813.s002"], "stats"=>{"downloads"=>18, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Neuropathology_of_16p13_11_Deletion_in_Epilepsy/126249", "title"=>"Neuropathology of 16p13.11 Deletion in Epilepsy", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2012-04-16 01:44:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/652613"], "description"=>"<p>LFB (A) and Alcian Blue (B) stains showed the location of the hamartia within the middle temporal gyrus (*). Small, round cells inside the hamartia were immunopositive for MAP2 as viewed at a low (C) and high (D) magnification. Scale = 100 µm (A–C), 20 µm (D).</p>", "links"=>[], "tags"=>["temporal", "cortex"], "article_id"=>323106, "categories"=>["Biological Sciences", "Cell Biology", "Genetics"], "users"=>["Joan Y. W. Liu", "Dalia Kasperavičiūtė", "Lillian Martinian", "Maria Thom", "Sanjay M. Sisodiya"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034813.g002", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Hamartia_in_the_temporal_cortex_of_Case_1_/323106", "title"=>"Hamartia in the temporal cortex of Case 1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-16 00:51:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/652435"], "description"=>"<p>The cortical lamination of the temporal cortex of Case 2 was normal, as compared to the MTLE case without <i>NDE1</i> deletion and non-epilepsy surgical controls. Scale = 200 µm.</p>", "links"=>[], "tags"=>["temporal", "cortex"], "article_id"=>322926, "categories"=>["Biological Sciences", "Cell Biology", "Genetics"], "users"=>["Joan Y. W. Liu", "Dalia Kasperavičiūtė", "Lillian Martinian", "Maria Thom", "Sanjay M. Sisodiya"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034813.g001", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_temporal_cortex_of_Case_2_/322926", "title"=>"The temporal cortex of Case 2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-16 00:48:46"}
  • {"files"=>["https://ndownloader.figshare.com/files/652963"], "description"=>"<p>MAP1B and calbindin-immunopositive cells were predominantly observed in the upper cortical layers, while SMI32-immunopositive cells and processes were mainly found in the lower cortical layers of MTLE cases with (A) or without <i>NDE1</i> deletion (B). Immunoreactivity of SMI94 was observed in the lower cortical layers and white matter of both cases. Scale = 200 µm (A, B).</p>", "links"=>[], "tags"=>["calbindin", "smi94-immunopositive", "labelling", "temporal", "cortex", "mtle"], "article_id"=>323451, "categories"=>["Biological Sciences", "Cell Biology", "Genetics"], "users"=>["Joan Y. W. Liu", "Dalia Kasperavičiūtė", "Lillian Martinian", "Maria Thom", "Sanjay M. Sisodiya"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034813.g004", "stats"=>{"downloads"=>1, "page_views"=>24, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MAP1B_SMI32_Calbindin_and_SMI94_immunopositive_labelling_in_the_temporal_cortex_of_Case_2_and_the_MTLE_control_/323451", "title"=>"MAP1B, SMI32, Calbindin and SMI94-immunopositive labelling in the temporal cortex of Case 2 and the MTLE control.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-16 00:57:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/654038"], "description"=>"<p>Clinical details of cases.</p>", "links"=>[], "tags"=>["details"], "article_id"=>324530, "categories"=>["Biological Sciences", "Cell Biology", "Genetics"], "users"=>["Joan Y. W. Liu", "Dalia Kasperavičiūtė", "Lillian Martinian", "Maria Thom", "Sanjay M. Sisodiya"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034813.t001", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Clinical_details_of_cases_/324530", "title"=>"Clinical details of cases.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2012-04-16 01:15:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/653166"], "description"=>"<p>A few numbers of parvalbumin-immunopositive cells were still observed in CA4 (A) and CA2 (B) of the sclerotic hippocampus of Case 2. Some parvalbumin-immunopositive processes and plexuses were observed around granule cells (A) and surviving pyramidal neurons in CA2 (B). CA = cornu Ammonis, GCL = granule cell layer. Scale = 20 µm (A, B).</p>", "links"=>[], "tags"=>["labelling", "hippocampus"], "article_id"=>323658, "categories"=>["Biological Sciences", "Cell Biology", "Genetics"], "users"=>["Joan Y. W. Liu", "Dalia Kasperavičiūtė", "Lillian Martinian", "Maria Thom", "Sanjay M. Sisodiya"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034813.g005", "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Parvalbumin_immunopositive_labelling_in_the_hippocampus_of_Case_2_/323658", "title"=>"Parvalbumin-immunopositive labelling in the hippocampus of Case 2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-16 01:00:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/653886"], "description"=>"<p>(A) Many MRP1-immunopositive cells and processes were observed in the hippocampus. (B) MRP1-immunopositive cells were also evident in the temporal cortex (usually around blood vessels). CA = cornu Ammonis, GCL = granule cell layer, BV = blood vessel. Scale = 50 µm (A), 20 µm (B).</p>", "links"=>[], "tags"=>["labelling", "temporal", "cortex", "hippocampus"], "article_id"=>324374, "categories"=>["Biological Sciences", "Cell Biology", "Genetics"], "users"=>["Joan Y. W. Liu", "Dalia Kasperavičiūtė", "Lillian Martinian", "Maria Thom", "Sanjay M. Sisodiya"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034813.g009", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_MRP1_immunopositive_labelling_in_the_temporal_cortex_and_hippocampus_of_Case_2_/324374", "title"=>"MRP1-immunopositive labelling in the temporal cortex and hippocampus of Case 2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-16 01:12:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/653558"], "description"=>"<p>In cortical layer I, DCX-immunopositive cells with a glial-like morphology clustered in groups of two or three (arrows, A). DCX-immunopositive cells with short, bipolar processes were occasionally observed in the upper cortical layers (A inset). Reelin-immunopositive cells were also observed in cortical layer I (B) and in deeper cortical layers of Case 2 (B, inset). Scale = 10 µm (A, B, insets).</p>", "links"=>[], "tags"=>["reelin-immunopositive", "labelling", "temporal", "cortex"], "article_id"=>324050, "categories"=>["Biological Sciences", "Cell Biology", "Genetics"], "users"=>["Joan Y. W. Liu", "Dalia Kasperavičiūtė", "Lillian Martinian", "Maria Thom", "Sanjay M. Sisodiya"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034813.g007", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_DCX_and_reelin_immunopositive_labelling_in_the_temporal_cortex_of_Case_2_/324050", "title"=>"DCX and reelin-immunopositive labelling in the temporal cortex of Case 2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-16 01:07:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/653985"], "description"=>"<p>An illustration showing deleted genes in 16p13.11 in Case 1 and Case 2.</p>", "links"=>[], "tags"=>["deleted", "genes"], "article_id"=>324479, "categories"=>["Biological Sciences", "Cell Biology", "Genetics"], "users"=>["Joan Y. W. Liu", "Dalia Kasperavičiūtė", "Lillian Martinian", "Maria Thom", "Sanjay M. Sisodiya"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0034813.g010", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_An_illustration_showing_deleted_genes_in_16p13_11_in_Case_1_and_Case_2_/324479", "title"=>"An illustration showing deleted genes in 16p13.11 in Case 1 and Case 2.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2012-04-16 01:14:39"}

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Relative Metric

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