Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A
Epileptic encephalopathies are a catastrophic group of epilepsies characterized by refractory seizures and cognitive arrest, often resulting from abnormal brain development. Here, we have identified an epileptic encephalopathy additionally featuring cerebral calcifications and coarse facial features...
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| Veröffentlicht in: | American journal of human genetics 2016-12, Vol.99 (6), p.1359-1367 |
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| creator | Han, Chanshuai Alkhater, Reem Froukh, Tawfiq Minassian, Arakel G. Galati, Melissa Liu, Rui Han Fotouhi, Maryam Sommerfeld, Julia Alfrook, Ayman J. Marshall, Christian Walker, Susan Bauer, Peter Scherer, Stephen W. Riess, Olaf Buchert, Rebecca Minassian, Berge A. McPherson, Peter S. |
| description | Epileptic encephalopathies are a catastrophic group of epilepsies characterized by refractory seizures and cognitive arrest, often resulting from abnormal brain development. Here, we have identified an epileptic encephalopathy additionally featuring cerebral calcifications and coarse facial features caused by recessive loss-of-function mutations in DENND5A. DENND5A contains a DENN domain, an evolutionarily ancient enzymatic module conferring guanine nucleotide exchange factor (GEF) activity to multiple proteins serving as GEFs for Rabs, which are key regulators of membrane trafficking. DENND5A is detected predominantly in neuronal tissues, and its highest levels occur during development. Knockdown of DENND5A leads to striking alterations in neuronal development. Mechanistically, these changes appear to result from upregulation of neurotrophin receptors, leading to enhanced downstream signaling. Thus, we have identified a link between a DENN domain protein and neuronal development, dysfunction of which is responsible for a form of epileptic encephalopathy. |
| doi_str_mv | 10.1016/j.ajhg.2016.10.006 |
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Here, we have identified an epileptic encephalopathy additionally featuring cerebral calcifications and coarse facial features caused by recessive loss-of-function mutations in DENND5A. DENND5A contains a DENN domain, an evolutionarily ancient enzymatic module conferring guanine nucleotide exchange factor (GEF) activity to multiple proteins serving as GEFs for Rabs, which are key regulators of membrane trafficking. DENND5A is detected predominantly in neuronal tissues, and its highest levels occur during development. Knockdown of DENND5A leads to striking alterations in neuronal development. Mechanistically, these changes appear to result from upregulation of neurotrophin receptors, leading to enhanced downstream signaling. Thus, we have identified a link between a DENN domain protein and neuronal development, dysfunction of which is responsible for a form of epileptic encephalopathy.</description><identifier>ISSN: 0002-9297</identifier><identifier>EISSN: 1537-6605</identifier><identifier>DOI: 10.1016/j.ajhg.2016.10.006</identifier><identifier>PMID: 27866705</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Adolescent ; Animals ; Brain ; Brain - pathology ; Child ; Consanguinity ; Convulsions & seizures ; Epilepsy ; Epilepsy - genetics ; Female ; Humans ; Male ; Mutation ; Neurons ; Neurons - metabolism ; PC12 Cells ; Pedigree ; Proteins ; rab GTP-Binding Proteins - genetics ; Rats</subject><ispartof>American journal of human genetics, 2016-12, Vol.99 (6), p.1359-1367</ispartof><rights>2016 American Society of Human Genetics</rights><rights>Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.</rights><rights>Copyright Cell Press Dec 1, 2016</rights><rights>2016 American Society of Human Genetics. 2016 American Society of Human Genetics</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c483t-92739042bf5206dfaf39265056c450f316ebf8b42316968da4d4ac4fa772c5243</citedby><cites>FETCH-LOGICAL-c483t-92739042bf5206dfaf39265056c450f316ebf8b42316968da4d4ac4fa772c5243</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142110/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.ajhg.2016.10.006$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,3548,27922,27923,45993,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27866705$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Han, Chanshuai</creatorcontrib><creatorcontrib>Alkhater, Reem</creatorcontrib><creatorcontrib>Froukh, Tawfiq</creatorcontrib><creatorcontrib>Minassian, Arakel G.</creatorcontrib><creatorcontrib>Galati, Melissa</creatorcontrib><creatorcontrib>Liu, Rui Han</creatorcontrib><creatorcontrib>Fotouhi, Maryam</creatorcontrib><creatorcontrib>Sommerfeld, Julia</creatorcontrib><creatorcontrib>Alfrook, Ayman J.</creatorcontrib><creatorcontrib>Marshall, Christian</creatorcontrib><creatorcontrib>Walker, Susan</creatorcontrib><creatorcontrib>Bauer, Peter</creatorcontrib><creatorcontrib>Scherer, Stephen W.</creatorcontrib><creatorcontrib>Riess, Olaf</creatorcontrib><creatorcontrib>Buchert, Rebecca</creatorcontrib><creatorcontrib>Minassian, Berge A.</creatorcontrib><creatorcontrib>McPherson, Peter S.</creatorcontrib><title>Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A</title><title>American journal of human genetics</title><addtitle>Am J Hum Genet</addtitle><description>Epileptic encephalopathies are a catastrophic group of epilepsies characterized by refractory seizures and cognitive arrest, often resulting from abnormal brain development. Here, we have identified an epileptic encephalopathy additionally featuring cerebral calcifications and coarse facial features caused by recessive loss-of-function mutations in DENND5A. DENND5A contains a DENN domain, an evolutionarily ancient enzymatic module conferring guanine nucleotide exchange factor (GEF) activity to multiple proteins serving as GEFs for Rabs, which are key regulators of membrane trafficking. DENND5A is detected predominantly in neuronal tissues, and its highest levels occur during development. Knockdown of DENND5A leads to striking alterations in neuronal development. Mechanistically, these changes appear to result from upregulation of neurotrophin receptors, leading to enhanced downstream signaling. Thus, we have identified a link between a DENN domain protein and neuronal development, dysfunction of which is responsible for a form of epileptic encephalopathy.</description><subject>Adolescent</subject><subject>Animals</subject><subject>Brain</subject><subject>Brain - pathology</subject><subject>Child</subject><subject>Consanguinity</subject><subject>Convulsions & seizures</subject><subject>Epilepsy</subject><subject>Epilepsy - genetics</subject><subject>Female</subject><subject>Humans</subject><subject>Male</subject><subject>Mutation</subject><subject>Neurons</subject><subject>Neurons - metabolism</subject><subject>PC12 Cells</subject><subject>Pedigree</subject><subject>Proteins</subject><subject>rab GTP-Binding Proteins - genetics</subject><subject>Rats</subject><issn>0002-9297</issn><issn>1537-6605</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kcFu1DAQhi0EotvCC3BAlrj0sovt2E4iIaRqm7ZIZbnAFctxJhtH2TjYTsW-PY62VMCBk0f2N79m_CH0hpINJVS-7ze67_Yblup0sSFEPkMrKrJ8LSURz9GKEMLWJSvzM3QeQk8IpQXJXqIzlhdS5kSs0PdqsgNM0RpcjQamTg9u0rE74q2eAzS4PuLPc9TRujFgO-LYAb6d9WhHwLvZDOCibQBXP02nxz3gG22i8_i62u2uxdUr9KLVQ4DXj-cF-nZTfd3ere-_3H7aXt2vDS-ymGbMs5JwVreCEdm0us1KJgUR0nBB2oxKqNui5ixVpSwazRuuDW91njMjGM8u0MdT7jTXB2gMjNHrQU3eHrQ_Kqet-vtltJ3auwclKGeUkhRw-Rjg3Y8ZQlQHGwwMgx7BzUHRgjPBJWMsoe_-QXs3-zGtt1AFKUROs0SxE2W8C8FD-zQMJWrRp3q16FOLvuUu6UtNb_9c46nlt68EfDgBkD7zwYJXwVhI4hrrwUTVOPu__F_wTqqz</recordid><startdate>20161201</startdate><enddate>20161201</enddate><creator>Han, Chanshuai</creator><creator>Alkhater, Reem</creator><creator>Froukh, Tawfiq</creator><creator>Minassian, Arakel G.</creator><creator>Galati, Melissa</creator><creator>Liu, Rui Han</creator><creator>Fotouhi, Maryam</creator><creator>Sommerfeld, Julia</creator><creator>Alfrook, Ayman J.</creator><creator>Marshall, Christian</creator><creator>Walker, Susan</creator><creator>Bauer, Peter</creator><creator>Scherer, Stephen W.</creator><creator>Riess, Olaf</creator><creator>Buchert, Rebecca</creator><creator>Minassian, Berge A.</creator><creator>McPherson, Peter S.</creator><general>Elsevier Inc</general><general>Cell Press</general><general>Elsevier</general><scope>6I.</scope><scope>AAFTH</scope><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>7QP</scope><scope>7TK</scope><scope>7TM</scope><scope>7U7</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20161201</creationdate><title>Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A</title><author>Han, Chanshuai ; Alkhater, Reem ; Froukh, Tawfiq ; Minassian, Arakel G. ; Galati, Melissa ; Liu, Rui Han ; Fotouhi, Maryam ; Sommerfeld, Julia ; Alfrook, Ayman J. ; Marshall, Christian ; Walker, Susan ; Bauer, Peter ; Scherer, Stephen W. ; Riess, Olaf ; Buchert, Rebecca ; Minassian, Berge A. ; McPherson, Peter S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c483t-92739042bf5206dfaf39265056c450f316ebf8b42316968da4d4ac4fa772c5243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adolescent</topic><topic>Animals</topic><topic>Brain</topic><topic>Brain - pathology</topic><topic>Child</topic><topic>Consanguinity</topic><topic>Convulsions & seizures</topic><topic>Epilepsy</topic><topic>Epilepsy - genetics</topic><topic>Female</topic><topic>Humans</topic><topic>Male</topic><topic>Mutation</topic><topic>Neurons</topic><topic>Neurons - metabolism</topic><topic>PC12 Cells</topic><topic>Pedigree</topic><topic>Proteins</topic><topic>rab GTP-Binding Proteins - genetics</topic><topic>Rats</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Han, Chanshuai</creatorcontrib><creatorcontrib>Alkhater, Reem</creatorcontrib><creatorcontrib>Froukh, Tawfiq</creatorcontrib><creatorcontrib>Minassian, Arakel G.</creatorcontrib><creatorcontrib>Galati, Melissa</creatorcontrib><creatorcontrib>Liu, Rui Han</creatorcontrib><creatorcontrib>Fotouhi, Maryam</creatorcontrib><creatorcontrib>Sommerfeld, Julia</creatorcontrib><creatorcontrib>Alfrook, Ayman J.</creatorcontrib><creatorcontrib>Marshall, Christian</creatorcontrib><creatorcontrib>Walker, Susan</creatorcontrib><creatorcontrib>Bauer, Peter</creatorcontrib><creatorcontrib>Scherer, Stephen W.</creatorcontrib><creatorcontrib>Riess, Olaf</creatorcontrib><creatorcontrib>Buchert, Rebecca</creatorcontrib><creatorcontrib>Minassian, Berge A.</creatorcontrib><creatorcontrib>McPherson, Peter S.</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>American journal of human genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Han, Chanshuai</au><au>Alkhater, Reem</au><au>Froukh, Tawfiq</au><au>Minassian, Arakel G.</au><au>Galati, Melissa</au><au>Liu, Rui Han</au><au>Fotouhi, Maryam</au><au>Sommerfeld, Julia</au><au>Alfrook, Ayman J.</au><au>Marshall, Christian</au><au>Walker, Susan</au><au>Bauer, Peter</au><au>Scherer, Stephen W.</au><au>Riess, Olaf</au><au>Buchert, Rebecca</au><au>Minassian, Berge A.</au><au>McPherson, Peter S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A</atitle><jtitle>American journal of human genetics</jtitle><addtitle>Am J Hum Genet</addtitle><date>2016-12-01</date><risdate>2016</risdate><volume>99</volume><issue>6</issue><spage>1359</spage><epage>1367</epage><pages>1359-1367</pages><issn>0002-9297</issn><eissn>1537-6605</eissn><abstract>Epileptic encephalopathies are a catastrophic group of epilepsies characterized by refractory seizures and cognitive arrest, often resulting from abnormal brain development. Here, we have identified an epileptic encephalopathy additionally featuring cerebral calcifications and coarse facial features caused by recessive loss-of-function mutations in DENND5A. DENND5A contains a DENN domain, an evolutionarily ancient enzymatic module conferring guanine nucleotide exchange factor (GEF) activity to multiple proteins serving as GEFs for Rabs, which are key regulators of membrane trafficking. DENND5A is detected predominantly in neuronal tissues, and its highest levels occur during development. Knockdown of DENND5A leads to striking alterations in neuronal development. Mechanistically, these changes appear to result from upregulation of neurotrophin receptors, leading to enhanced downstream signaling. Thus, we have identified a link between a DENN domain protein and neuronal development, dysfunction of which is responsible for a form of epileptic encephalopathy.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>27866705</pmid><doi>10.1016/j.ajhg.2016.10.006</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adolescent Animals Brain Brain - pathology Child Consanguinity Convulsions & seizures Epilepsy Epilepsy - genetics Female Humans Male Mutation Neurons Neurons - metabolism PC12 Cells Pedigree Proteins rab GTP-Binding Proteins - genetics Rats |
| title | Epileptic Encephalopathy Caused by Mutations in the Guanine Nucleotide Exchange Factor DENND5A |
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