Somatic mosaicism of the PI3K‐AKT‐MTOR pathway is associated with hemimegalencephaly in fetal brains
It is known that somatic activation of PI3K–AKT–MTOR signaling causes malformations of cortical development varying from hemimegalencephaly to focal cortical dysplasia. However, there have been few reports of fetal cases. Here we report two fetal cases of hemimegalencephaly, one associated with mosa...
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| Veröffentlicht in: | Neuropathology 2023-04, Vol.43 (2), p.190-196 |
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| creator | Itoh, Kyoko Pooh, Ritsuko Shimokawa, Osamu Fushiki, Shinji |
| description | It is known that somatic activation of PI3K–AKT–MTOR signaling causes malformations of cortical development varying from hemimegalencephaly to focal cortical dysplasia. However, there have been few reports of fetal cases. Here we report two fetal cases of hemimegalencephaly, one associated with mosaic mutations in PIK3CA and another in AKT1. Both brains showed polymicrogyria, multiple subarachnoidal, subcortical, and subventricular heterotopia resulting from abnormal proliferation of neural stem/progenitor cells, cell differentiation, and migration of neuroblasts. Scattered cell nests immunoreactive for phosphorylated‐S6 ribosomal protein (P‐RPS6) (Ser240/244) were observed in the polymicrogyria‐like cortical plate, intermediate zone, and arachnoid space, suggesting that the PI3K–AKT–MTOR pathway was actually activated in these cells. Pathological analyses could shed light on the mechanisms involved in disrupted brain development in the somatic mosaicism of the PI3K‐AKT–MTOR pathway. |
| doi_str_mv | 10.1111/neup.12875 |
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However, there have been few reports of fetal cases. Here we report two fetal cases of hemimegalencephaly, one associated with mosaic mutations in PIK3CA and another in AKT1. Both brains showed polymicrogyria, multiple subarachnoidal, subcortical, and subventricular heterotopia resulting from abnormal proliferation of neural stem/progenitor cells, cell differentiation, and migration of neuroblasts. Scattered cell nests immunoreactive for phosphorylated‐S6 ribosomal protein (P‐RPS6) (Ser240/244) were observed in the polymicrogyria‐like cortical plate, intermediate zone, and arachnoid space, suggesting that the PI3K–AKT–MTOR pathway was actually activated in these cells. Pathological analyses could shed light on the mechanisms involved in disrupted brain development in the somatic mosaicism of the PI3K‐AKT–MTOR pathway.</description><identifier>ISSN: 0919-6544</identifier><identifier>EISSN: 1440-1789</identifier><identifier>DOI: 10.1111/neup.12875</identifier><identifier>PMID: 36325654</identifier><language>eng</language><publisher>Melbourne: John Wiley & Sons Australia, Ltd</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; AKT1 ; AKT1 protein ; Brain - pathology ; Cell differentiation ; Cell proliferation ; Dysplasia ; Fetuses ; hemimegalencephaly ; Hemimegalencephaly - genetics ; Hemimegalencephaly - metabolism ; Hemimegalencephaly - pathology ; heterotopia ; Humans ; Mosaicism ; Mutation ; Nests ; Neural stem cells ; Phosphatidylinositol 3-Kinases - metabolism ; PIK3CA ; Polymicrogyria ; Polymicrogyria - metabolism ; Polymicrogyria - pathology ; Progenitor cells ; Proto-Oncogene Proteins c-akt - metabolism ; TOR protein ; TOR Serine-Threonine Kinases - metabolism</subject><ispartof>Neuropathology, 2023-04, Vol.43 (2), p.190-196</ispartof><rights>2022 Japanese Society of Neuropathology.</rights><rights>2023 Japanese Society of Neuropathology</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3485-880f3e8b3bb50b6c5022599cf9100f08c78c4f84ed7b46fb46ac26038bd8e2c03</citedby><cites>FETCH-LOGICAL-c3485-880f3e8b3bb50b6c5022599cf9100f08c78c4f84ed7b46fb46ac26038bd8e2c03</cites><orcidid>0000-0001-8369-8800</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fneup.12875$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fneup.12875$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36325654$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Itoh, Kyoko</creatorcontrib><creatorcontrib>Pooh, Ritsuko</creatorcontrib><creatorcontrib>Shimokawa, Osamu</creatorcontrib><creatorcontrib>Fushiki, Shinji</creatorcontrib><title>Somatic mosaicism of the PI3K‐AKT‐MTOR pathway is associated with hemimegalencephaly in fetal brains</title><title>Neuropathology</title><addtitle>Neuropathology</addtitle><description>It is known that somatic activation of PI3K–AKT–MTOR signaling causes malformations of cortical development varying from hemimegalencephaly to focal cortical dysplasia. However, there have been few reports of fetal cases. Here we report two fetal cases of hemimegalencephaly, one associated with mosaic mutations in PIK3CA and another in AKT1. Both brains showed polymicrogyria, multiple subarachnoidal, subcortical, and subventricular heterotopia resulting from abnormal proliferation of neural stem/progenitor cells, cell differentiation, and migration of neuroblasts. Scattered cell nests immunoreactive for phosphorylated‐S6 ribosomal protein (P‐RPS6) (Ser240/244) were observed in the polymicrogyria‐like cortical plate, intermediate zone, and arachnoid space, suggesting that the PI3K–AKT–MTOR pathway was actually activated in these cells. Pathological analyses could shed light on the mechanisms involved in disrupted brain development in the somatic mosaicism of the PI3K‐AKT–MTOR pathway.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>AKT1</subject><subject>AKT1 protein</subject><subject>Brain - pathology</subject><subject>Cell differentiation</subject><subject>Cell proliferation</subject><subject>Dysplasia</subject><subject>Fetuses</subject><subject>hemimegalencephaly</subject><subject>Hemimegalencephaly - genetics</subject><subject>Hemimegalencephaly - metabolism</subject><subject>Hemimegalencephaly - pathology</subject><subject>heterotopia</subject><subject>Humans</subject><subject>Mosaicism</subject><subject>Mutation</subject><subject>Nests</subject><subject>Neural stem cells</subject><subject>Phosphatidylinositol 3-Kinases - metabolism</subject><subject>PIK3CA</subject><subject>Polymicrogyria</subject><subject>Polymicrogyria - metabolism</subject><subject>Polymicrogyria - pathology</subject><subject>Progenitor cells</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>TOR protein</subject><subject>TOR Serine-Threonine Kinases - metabolism</subject><issn>0919-6544</issn><issn>1440-1789</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kM1KAzEQx4MotlYvPoAEvAlbk81-JMciVUurLdqelySbuCn75WZL6c1H8Bl9ElO3enRgZg7z4z_wA-ASoyF2dVuqTT3EPo3DI9DHQYA8HFN2DPqIYeZFYRD0wJm1a4RwzHx6CnokIn7oDn2QvVYFb42ERWW5kcYWsNKwzRRcTMj06-NzNF26-bScv8Cat9mW76CxkFtbScNblcKtaTOYqcIU6o3nqpSqznjuqBJq1fIcioab0p6DE81zqy4OewBW9-Pl3aM3mz9M7kYzT5KAhh6lSBNFBREiRCKSIfL9kDGpGUZIIypjKgNNA5XGIoi0ay79CBEqUqp8icgAXHe5dVO9b5Rtk3W1aUr3MvFjRmJnwK0BuOko2VTWNkondWMK3uwSjJK91GQvNfmR6uCrQ-RGFCr9Q38tOgB3wNbkavdPVPI8Xi260G9O8oO3</recordid><startdate>202304</startdate><enddate>202304</enddate><creator>Itoh, Kyoko</creator><creator>Pooh, Ritsuko</creator><creator>Shimokawa, Osamu</creator><creator>Fushiki, Shinji</creator><general>John Wiley & Sons Australia, Ltd</general><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>K9.</scope><orcidid>https://orcid.org/0000-0001-8369-8800</orcidid></search><sort><creationdate>202304</creationdate><title>Somatic mosaicism of the PI3K‐AKT‐MTOR pathway is associated with hemimegalencephaly in fetal brains</title><author>Itoh, Kyoko ; Pooh, Ritsuko ; Shimokawa, Osamu ; Fushiki, Shinji</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3485-880f3e8b3bb50b6c5022599cf9100f08c78c4f84ed7b46fb46ac26038bd8e2c03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>AKT1</topic><topic>AKT1 protein</topic><topic>Brain - pathology</topic><topic>Cell differentiation</topic><topic>Cell proliferation</topic><topic>Dysplasia</topic><topic>Fetuses</topic><topic>hemimegalencephaly</topic><topic>Hemimegalencephaly - genetics</topic><topic>Hemimegalencephaly - metabolism</topic><topic>Hemimegalencephaly - pathology</topic><topic>heterotopia</topic><topic>Humans</topic><topic>Mosaicism</topic><topic>Mutation</topic><topic>Nests</topic><topic>Neural stem cells</topic><topic>Phosphatidylinositol 3-Kinases - metabolism</topic><topic>PIK3CA</topic><topic>Polymicrogyria</topic><topic>Polymicrogyria - metabolism</topic><topic>Polymicrogyria - pathology</topic><topic>Progenitor cells</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>TOR protein</topic><topic>TOR Serine-Threonine Kinases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Itoh, Kyoko</creatorcontrib><creatorcontrib>Pooh, Ritsuko</creatorcontrib><creatorcontrib>Shimokawa, Osamu</creatorcontrib><creatorcontrib>Fushiki, Shinji</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Neurosciences Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><jtitle>Neuropathology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Itoh, Kyoko</au><au>Pooh, Ritsuko</au><au>Shimokawa, Osamu</au><au>Fushiki, Shinji</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Somatic mosaicism of the PI3K‐AKT‐MTOR pathway is associated with hemimegalencephaly in fetal brains</atitle><jtitle>Neuropathology</jtitle><addtitle>Neuropathology</addtitle><date>2023-04</date><risdate>2023</risdate><volume>43</volume><issue>2</issue><spage>190</spage><epage>196</epage><pages>190-196</pages><issn>0919-6544</issn><eissn>1440-1789</eissn><abstract>It is known that somatic activation of PI3K–AKT–MTOR signaling causes malformations of cortical development varying from hemimegalencephaly to focal cortical dysplasia. However, there have been few reports of fetal cases. Here we report two fetal cases of hemimegalencephaly, one associated with mosaic mutations in PIK3CA and another in AKT1. Both brains showed polymicrogyria, multiple subarachnoidal, subcortical, and subventricular heterotopia resulting from abnormal proliferation of neural stem/progenitor cells, cell differentiation, and migration of neuroblasts. Scattered cell nests immunoreactive for phosphorylated‐S6 ribosomal protein (P‐RPS6) (Ser240/244) were observed in the polymicrogyria‐like cortical plate, intermediate zone, and arachnoid space, suggesting that the PI3K–AKT–MTOR pathway was actually activated in these cells. Pathological analyses could shed light on the mechanisms involved in disrupted brain development in the somatic mosaicism of the PI3K‐AKT–MTOR pathway.</abstract><cop>Melbourne</cop><pub>John Wiley & Sons Australia, Ltd</pub><pmid>36325654</pmid><doi>10.1111/neup.12875</doi><tpages>7</tpages><orcidid>https://orcid.org/0000-0001-8369-8800</orcidid></addata></record> |
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| subjects | 1-Phosphatidylinositol 3-kinase AKT protein AKT1 AKT1 protein Brain - pathology Cell differentiation Cell proliferation Dysplasia Fetuses hemimegalencephaly Hemimegalencephaly - genetics Hemimegalencephaly - metabolism Hemimegalencephaly - pathology heterotopia Humans Mosaicism Mutation Nests Neural stem cells Phosphatidylinositol 3-Kinases - metabolism PIK3CA Polymicrogyria Polymicrogyria - metabolism Polymicrogyria - pathology Progenitor cells Proto-Oncogene Proteins c-akt - metabolism TOR protein TOR Serine-Threonine Kinases - metabolism |
| title | Somatic mosaicism of the PI3K‐AKT‐MTOR pathway is associated with hemimegalencephaly in fetal brains |
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