{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T14:40:11Z","timestamp":1776350411662,"version":"3.51.2"},"reference-count":31,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T00:00:00Z","timestamp":1744761600000},"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":["R24OD031447"],"award-info":[{"award-number":["R24OD031447"]}],"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":["R24OD022005"],"award-info":[{"award-number":["R24OD022005"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,5,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Laminin B1 (LAMB1) is one of the extracellular matrix (ECM) proteins that make up the basement membrane. Early frameshift, late frameshift, and missense variants in LAMB1 have been reported to cause rare monogenic neurological disorders that are collectively known as LAMB1-related leukoencephalopathy. Although there is some genotype\u2013phenotype correlation, functional consequences of pathogenic LAMB1 variants are largely unknown. In this study, we aimed to elucidate function of the fly ortholog of this gene (LanB1) in the nervous system and to further study the functional consequences of the LAMB1 variants using Drosophila melanogaster. We found that the LanB1 gene is expressed on the surface of adult fly brains in a subset of glia cells. We further found that LanB1 protein localizes to the blood\u2013brain barrier (BBB) in adult fly brains and knockdown of LanB1 in the BBB resulted in short life span and locomotor defects. Although human LAMB1 was not able to function in flies, in vivo overexpression and rescue experiments using analogous variants in fly LanB1 suggested that the frameshift variants behave as strong loss-of-function (LoF) alleles whereas a missense variant functions as a milder LoF allele. In vitro assay in HEK293T cells revealed that late-truncated LAMB1 is uniquely detected as a monomer in the culture medium, which might be the basis of dominant inheritance of these variants through a gain-of-function mechanism. Our data contributes to the understanding of the ECM component of the fly BBB and lays the foundation to unravel the molecular consequences of different pathogenic variants in LAMB1.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf050","type":"journal-article","created":{"date-parts":[[2025,4,16]],"date-time":"2025-04-16T13:42:27Z","timestamp":1744810947000},"page":"990-999","source":"Crossref","is-referenced-by-count":2,"title":["Functional analysis of pathogenic variants in <i>LAMB1<\/i>-related leukoencephalopathy reveals genotype\u2013phenotype correlations and suggests its role in glial cells"],"prefix":"10.1093","volume":"34","author":[{"given":"Rei","family":"Yasuda","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , One Baylor Plaza, Houston, TX 77030 ,","place":["United States"]},{"name":"Jan and Duncan Neurological Research Institute, Texas Children's Hospital , 1250 Moursund St, Houston, TX 77030 ,","place":["United States"]},{"name":"Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirokazu","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , One Baylor Plaza, Houston, TX 77030 ,","place":["United States"]},{"name":"Jan and Duncan Neurological Research Institute, Texas Children's Hospital , 1250 Moursund St, Houston, TX 77030 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mikiko","family":"Oka","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , One Baylor Plaza, Houston, TX 77030 ,","place":["United States"]},{"name":"Jan and Duncan Neurological Research Institute, Texas Children's Hospital , 1250 Moursund St, Houston, TX 77030 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung-Wan","family":"Mok","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , One Baylor Plaza, Houston, TX 77030 ,","place":["United States"]},{"name":"Jan and Duncan Neurological Research Institute, Texas Children's Hospital , 1250 Moursund St, Houston, TX 77030 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marium","family":"Waqar","sequence":"additional","affiliation":[{"name":"Department of Biology and Biochemistry, University of Houston , 3455 Cullen Blvd, Houston, TX 77204 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brigitte","family":"Dauwalder","sequence":"additional","affiliation":[{"name":"Department of Biology and Biochemistry, University of Houston , 3455 Cullen Blvd, Houston, TX 77204 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oguz","family":"Kanca","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , One Baylor Plaza, Houston, TX 77030 ,","place":["United States"]},{"name":"Jan and Duncan Neurological Research Institute, Texas Children's Hospital , 1250 Moursund St, Houston, TX 77030 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshiki","family":"Mizuno","sequence":"additional","affiliation":[{"name":"Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine , 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566 ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinya","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine , One Baylor Plaza, Houston, TX 77030 ,","place":["United States"]},{"name":"Jan and Duncan Neurological Research Institute, Texas Children's Hospital , 1250 Moursund St, Houston, TX 77030 ,","place":["United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2025,4,16]]},"reference":[{"key":"2025052712530255100_ref1","doi-asserted-by":"crossref","first-page":"48","DOI":"10.4161\/cam.22826","article-title":"The laminin family","volume":"7","author":"Aumailley","year":"2013","journal-title":"Cell Adhes Migr"},{"key":"2025052712530255100_ref2","doi-asserted-by":"crossref","first-page":"10189","DOI":"10.1073\/pnas.94.19.10189","article-title":"The alpha chain of laminin-1 is independently secreted and drives secretion of its beta- and gamma-chain partners","volume":"94","author":"Yurchenco","year":"1997","journal-title":"Proc Natl Acad Sci 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mutations","volume":"84","author":"Tonduti","year":"2015","journal-title":"Neurology"},{"key":"2025052712530255100_ref6","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1111\/cge.13378","article-title":"Bilateral cerebellar cysts and cerebral white matter lesions with cortical dysgenesis: expanding the phenotype of LAMB1 gene mutations","volume":"94","author":"Okazaki","year":"2018","journal-title":"Clin Genet"},{"key":"2025052712530255100_ref7","doi-asserted-by":"crossref","first-page":"e442","DOI":"10.1212\/NXG.0000000000000442","article-title":"Adult-onset leukoencephalopathy with homozygous LAMB1 missense mutation","volume":"6","author":"Yasuda","year":"2020","journal-title":"Neurol Genet"},{"key":"2025052712530255100_ref8","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1002\/ana.26242","article-title":"End-truncated LAMB1 causes a hippocampal memory defect and a leukoencephalopathy","volume":"90","author":"Aloui","year":"2021","journal-title":"Ann 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