{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T06:50:02Z","timestamp":1790664602116,"version":"4.1.0"},"reference-count":21,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,2,14]],"date-time":"2018-02-14T00:00:00Z","timestamp":1518566400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["Grant R01NS049117\u201001"],"award-info":[{"award-number":["Grant R01NS049117\u201001"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2018,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Monogenic defects of synaptic vesicle (<jats:styled-content style=\"fixed-case\">SV<\/jats:styled-content>) homeostasis have been implicated in many neurologic diseases, including autism, epilepsy, and movement disorders. In addition, abnormal vesicle exocytosis has been associated with several endocrine dysfunctions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We report an 11\u00a0year old girl with learning disabilities, tremors, ataxia, transient hyperglycemia, and muscle fatigability responsive to albuterol sulfate. Failure of neuromuscular transmission was confirmed by single fiber electromyography. Electron microscopy of motor nerve terminals revealed marked reduction in <jats:styled-content style=\"fixed-case\">SV<\/jats:styled-content> density, double\u2010membrane\u2010bound sacs containing <jats:styled-content style=\"fixed-case\">SV<\/jats:styled-content>s, abundant endosomes, and degenerative lamellar bodies. The patient underwent whole exome sequencing (<jats:styled-content style=\"fixed-case\">WES<\/jats:styled-content>) and relevant sequence variants were expressed and studied in a mammalian cell line.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Chromosomal microarray studies and next generation sequencing (<jats:styled-content style=\"fixed-case\">NGS<\/jats:styled-content>) of mitochondrial <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> were unrevealing; however, <jats:styled-content style=\"fixed-case\">NGS<\/jats:styled-content> of genomic <jats:styled-content style=\"fixed-case\">DNA<\/jats:styled-content> showed two rare sequence variants in the gene encoding rabphilin 3a <jats:italic>(<jats:styled-content style=\"fixed-case\">RPH<\/jats:styled-content>3A)<\/jats:italic>. The paternally inherited variant c.806\u00a0G&gt;A (p.Arg269Gln) involves a substitution of a conserved residue in the linker region, while the maternally inherited variant c.1390\u00a0G&gt;T (p.Val464Leu) involves a conserved amino acid substitution in the highly conserved C2A region. Expression studies revealed that p.Arg269Gln strongly impairs the binding of rabphilin 3a to 14\u20103\u20103, which is a proposed regulator of synaptic transmission and plasticity. In contrast, the binding of rabphilin 3a to 14\u20103\u20103 is only marginally impaired by p.Val464Leu; thus, the pathogenic role of p.Val464Leu remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>In summary, we report a patient with a multisystem neurologic disorder and altered <jats:styled-content style=\"fixed-case\">SV<\/jats:styled-content> regulation attributed to defects in <jats:italic><jats:styled-content style=\"fixed-case\">RPH<\/jats:styled-content>3A<\/jats:italic>, which grants further studies of this gene in human disorders of synaptic transmission.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.370","type":"journal-article","created":{"date-parts":[[2018,2,14]],"date-time":"2018-02-14T05:10:41Z","timestamp":1518585041000},"page":"434-440","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Presynaptic congenital myasthenic syndrome with altered synaptic vesicle homeostasis linked to compound heterozygous sequence variants in <i><scp>RPH<\/scp>3A<\/i>"],"prefix":"10.1002","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0918-0760","authenticated-orcid":false,"given":"Ricardo A.","family":"Maselli","sequence":"first","affiliation":[{"name":"Department of Neurology University of California Davis Sacramento CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"V\u00e1zquez","sequence":"additional","affiliation":[{"name":"Department of Neurology University of California Davis Sacramento CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leah","family":"Schrumpf","sequence":"additional","affiliation":[{"name":"Department of Neurology University of California Davis Sacramento CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Arredondo","sequence":"additional","affiliation":[{"name":"Department of Neurology University of California Davis Sacramento CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marian","family":"Lara","sequence":"additional","affiliation":[{"name":"Department of Neurology University of California Davis Sacramento CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan B.","family":"Strober","sequence":"additional","affiliation":[{"name":"Department of Neurology University of California San Francisco San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Pytel","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Chicago Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert L.","family":"Wollmann","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Chicago Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Ferns","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology and Pain Medicine University of California Davis Sacramento CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,2,14]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.111.2.243"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.40.23667"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.270.28.16714"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2014.01.008"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awt010"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M804094200"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.emboj.7601165"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1212\/NXG.0000000000000105"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(14)70201-7"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-15-05461.2001"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2014.08.007"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.50.31775"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tins.2011.02.006"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awm072"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.19-14-05834.1999"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/acn3.387"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000001079"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.13.4.2061"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.21-23-09255.2001"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M212801200"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M507173200"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fmgg3.370","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.370","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,22]],"date-time":"2023-09-22T15:29:48Z","timestamp":1695396588000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.370"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,2,14]]},"references-count":21,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2018,5]]}},"alternative-id":["10.1002\/mgg3.370"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.370","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,2,14]]},"assertion":[{"value":"2017-08-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2017-11-20","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-02-14","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}