{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T12:35:06Z","timestamp":1792154106741,"version":"4.4.0"},"reference-count":52,"publisher":"BMJ","issue":"8","funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"publisher","award":["R01EY033391"],"award-info":[{"award-number":["R01EY033391"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"name":"NIH"},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["R01NS117698"],"award-info":[{"award-number":["R01NS117698"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2024,4,14]]},"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Pontocerebellar hypoplasia (PCH) may present with supratentorial phenotypes and is often accompanied by microcephaly. Damaging mutations in the X-linked gene\n                      <jats:italic>CASK<\/jats:italic>\n                      produce self-limiting microcephaly with PCH in females but are often lethal in males. CASK deficiency leads to early degeneration of cerebellar granule cells but its role in other regions of the brain remains uncertain.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Method<\/jats:title>\n                    <jats:p>\n                      We generated a conditional\n                      <jats:italic>Cask<\/jats:italic>\n                      knockout mice and deleted\n                      <jats:italic>Cask<\/jats:italic>\n                      ubiquitously after birth at different times. We examined the clinical features in several subjects with damaging mutations clustered in the central part of the CASK protein. We have performed phylogenetic analysis and RT-PCR to assess the splicing pattern within the same protein region and performed in silico structural analysis to examine the effect of splicing on the CASK\u2019s structure.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Result<\/jats:title>\n                    <jats:p>\n                      We demonstrate that deletion of murine\n                      <jats:italic>Cask<\/jats:italic>\n                      after adulthood does not affect survival but leads to cerebellar degeneration and ataxia over time. Intriguingly, damaging hemizygous\n                      <jats:italic>CASK<\/jats:italic>\n                      mutations in boys who display microcephaly and cerebral dysfunction but without PCH are known. These mutations are present in two vertebrate-specific\n                      <jats:italic>CASK<\/jats:italic>\n                      exons. These exons are subject to alternative splicing both in forebrain and hindbrain. Inclusion of these exons differentially affects the molecular structure and hence possibly the function\/s of the CASK C-terminus.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Loss of CASK function disproportionately affects the cerebellum. Clinical data, however, suggest that CASK may have additional vertebrate-specific function\/s that play a role in the mammalian forebrain. Thus, CASK has an ancient function shared between invertebrates and vertebrates as well as novel vertebrate-specific function\/s.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2023-109747","type":"journal-article","created":{"date-parts":[[2024,4,26]],"date-time":"2024-04-26T13:15:35Z","timestamp":1714137335000},"page":"759-768","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Genetic evidence for splicing-dependent structural and functional plasticity in CASK protein"],"prefix":"10.1136","volume":"61","author":[{"given":"Paras A","family":"Patel","sequence":"first","affiliation":[{"name":"Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leslie E W","family":"LaConte","sequence":"additional","affiliation":[{"name":"Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, USA"},{"name":"Basic Science Education, Virginia Tech Carilion School of Medicine, Roanoke, VA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Liang","sequence":"additional","affiliation":[{"name":"Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Cecere","sequence":"additional","affiliation":[{"name":"Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepa","family":"Rajan","sequence":"additional","affiliation":[{"name":"University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarika","family":"Srivastava","sequence":"additional","affiliation":[{"name":"Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, USA"},{"name":"Department of Genetics, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6922-9554","authenticated-orcid":false,"given":"Konark","family":"Mukherjee","sequence":"additional","affiliation":[{"name":"Fralin Biomedical Research Institute at VTC, Roanoke, Virginia, USA"},{"name":"Department of Genetics, The University of Alabama at Birmingham Heersink School of Medicine, Birmingham, Alabama, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,4,26]]},"reference":[{"key":"2025100521243364000_61.8.759.1","doi-asserted-by":"publisher","DOI":"10.1177\/0883073810380047"},{"key":"2025100521243364000_61.8.759.2","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-6-50"},{"key":"2025100521243364000_61.8.759.3","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2020-107497"},{"key":"2025100521243364000_61.8.759.4","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.braindev.2013.03.007","article-title":"A de novo CASK mutation in Pontocerebellar hypoplasia type 3 with early myoclonic epilepsy and Tetralogy of Fallot","volume":"36","author":"Nakamura","year":"2014","journal-title":"Brain Dev"},{"key":"2025100521243364000_61.8.759.5","doi-asserted-by":"crossref","DOI":"10.1093\/brain\/awr108","article-title":"Mutations of TSEN and CASK genes are prevalent in pontocerebellar hypoplasias type 2 and 4","volume":"135","author":"Valayannopoulos","year":"2012","journal-title":"Brain (Bacau)"},{"key":"2025100521243364000_61.8.759.6","doi-asserted-by":"crossref","DOI":"10.1186\/s13023-015-0256-3","article-title":"Phenotypic and molecular insights into CASK-related disorders in males","volume":"10","author":"Moog","year":"2015","journal-title":"Orphanet J Rare Dis"},{"key":"2025100521243364000_61.8.759.7","doi-asserted-by":"crossref","DOI":"10.1002\/mgg3.1426","article-title":"Survival of a male patient harboring CASK Arg27Ter Mutation to adolescence","volume":"8","author":"Mukherjee","year":"2020","journal-title":"Mol Genet Genomic Med"},{"key":"2025100521243364000_61.8.759.8","doi-asserted-by":"crossref","first-page":"1441","DOI":"10.1111\/j.1528-1167.2012.03548.x","article-title":"CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia","volume":"53","author":"Saitsu","year":"2012","journal-title":"Epilepsia"},{"key":"2025100521243364000_61.8.759.9","doi-asserted-by":"crossref","unstructured":"Patel PA , Hegert J , Cristian I , et al . 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