{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T16:53:58Z","timestamp":1787331238236,"version":"build-2736575974"},"reference-count":30,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T00:00:00Z","timestamp":1726617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01HD093570-01A1"],"award-info":[{"award-number":["1R01HD093570-01A1"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS095884, R33NS104384, R33NS106087, R01NS126193"],"award-info":[{"award-number":["R01NS095884, R33NS104384, R33NS106087, R01NS126193"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21NS131906"],"award-info":[{"award-number":["R21NS131906"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,12,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Erythrocyte membrane protein band 4.1 like 3 (EPB41L3: NM_012307.5), also known as DAL1, encodes the ubiquitously expressed, neuronally enriched 4.1B protein, part of the 4.1 superfamily of membrane-cytoskeleton adaptors. The 4.1B protein plays key roles in cell spreading, migration and cytoskeletal scaffolding that support oligodendrocyte axon adhesions essential for proper myelination.<\/jats:p>\n               <jats:p>We herein describe six individuals from five unrelated families with global developmental delay, intellectual disability, seizures, hypotonia, neuroregression and delayed myelination. Exome sequencing identified biallelic variants in EPB41L3 in all affected individuals: two nonsense [c.466C&amp;gt;T, p.(R156*); c.2776C&amp;gt;T, p.(R926*)] and three frameshift [c.666delT, p.(F222Lfs*46); c.2289dupC, p.(V764Rfs*19); c.948_949delTG, p.(A317Kfs*33)].<\/jats:p>\n               <jats:p>Quantitative-real time PCR and western blot analyses of human fibroblasts harbouring EPB41L3:c.666delT, p.(F222Lfs*46) indicated ablation of EPB41L3 mRNA and 4.1B protein expression. Inhibition of the nonsense mediated decay (NMD) pathway led to an upregulation of EPB41L3:c.666delT transcripts, supporting NMD as a pathogenic mechanism. Epb41l3-deficient mouse oligodendroglia cells showed significant reduction in mRNA expression of key myelin genes, reduced branching and increased apoptosis.<\/jats:p>\n               <jats:p>Our report provides the first clinical description of an autosomal recessive disorder associated with variants in EPB41L3, which we refer to as EPB41L3-associated developmental disorder (EADD). Moreover, our functional studies substantiate the pathogenicity of EPB41L3 hypothesized loss-of-function variants.<\/jats:p>","DOI":"10.1093\/brain\/awae299","type":"journal-article","created":{"date-parts":[[2024,9,18]],"date-time":"2024-09-18T20:10:09Z","timestamp":1726690209000},"page":"4033-4042","source":"Crossref","is-referenced-by-count":4,"title":["Biallelic <i>EPB41L3<\/i> variants underlie a developmental disorder with seizures and myelination defects"],"prefix":"10.1093","volume":"147","author":[{"given":"Elizabeth A","family":"Werren","sequence":"first","affiliation":[{"name":"Department of Human Genetics, University of Michigan Medical School , Ann Arbor, MI 48109 ,","place":["USA"]},{"name":"Advanced Precision Medicine Laboratory, The Jackson Laboratory for Genomic Medicine , Farmington, CT 06032 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillermo","family":"Rodriguez Bey","sequence":"additional","affiliation":[{"name":"Department 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,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minal V","family":"Kekatpure","sequence":"additional","affiliation":[{"name":"Department of Neurology, Division of Pediatric Neurology, Mazumdar Shaw Medical Center, Narayana Health , Bangalore 560099 ,","place":["India"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Afenjar","sequence":"additional","affiliation":[{"name":"Reference Center for Malformations and Congenital Diseases of the Cerebellum and Unit of Molecular Genetics, Department of Genetics, Trousseau Hospital, APHP Sorbonne University , Paris 75012 ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Qebibo","sequence":"additional","affiliation":[{"name":"Reference Center for Malformations and Congenital Diseases of the Cerebellum and Unit of Molecular Genetics, Department of Genetics, Trousseau Hospital, APHP Sorbonne University , Paris 75012 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