{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,3]],"date-time":"2026-11-03T15:03:00Z","timestamp":1793718180073,"version":"4.6.1"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T00:00:00Z","timestamp":1678838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>LAMA2-related muscular dystrophy (LAMA2 MD or MDC1A) is a devastating congenital muscular dystrophy that is caused by mutations in the LAMA2 gene encoding laminin-\u03b12, the long chain of several heterotrimeric laminins. Laminins are essential components of the extracellular matrix that interface with underlying cells. The pathology of LAMA2 MD patients is dominated by an early-onset, severe muscular dystrophy that ultimately leads to death by respiratory insufficiency. However, pathology in nonmuscle tissues has been described. Prior work in the dyW\/dyW mouse model for LAMA2 MD has shown that two linker proteins, mini-agrin and \u03b1LNNd, when expressed in skeletal muscle fibers, greatly increase survival from a few months up to more than 2 years. However, the restoration of skeletal muscle function accentuates the pathology in nonmuscle tissue in dyW\/dyW mice, first and foremost in the peripheral nerve resulting in paralysis of the hind limbs. We now show that the expression of the two linker proteins in all tissues ameliorates the muscular dystrophy and prevents the appearance of the hind limb paralysis. Importantly, the same ameliorating effect of the linker proteins was seen in dy3K\/dy3K mice, which represent the most severe mouse model of LAMA2 MD. In summary, these data show that the two linker proteins can compensate the loss of laminin-\u03b12 in muscle and peripheral nerve, which are the two organs most affected in LAMA2 MD. These results are of key importance for designing appropriate expression constructs for mini-agrin and \u03b1LNNd to develop a gene therapy for LAMA2 MD patients.<\/jats:p>","DOI":"10.1093\/pnasnexus\/pgad083","type":"journal-article","created":{"date-parts":[[2023,3,15]],"date-time":"2023-03-15T09:25:26Z","timestamp":1678872326000},"source":"Crossref","is-referenced-by-count":18,"title":["Nerve pathology is prevented by linker proteins in mouse models for\n                    <i>LAMA2<\/i>\n                    -related muscular dystrophy"],"prefix":"10.1093","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2497-7719","authenticated-orcid":false,"given":"Judith R","family":"Reinhard","sequence":"first","affiliation":[{"name":"Biozentrum, University of Basel , 4056 Basel , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0490-1538","authenticated-orcid":false,"given":"Emanuela","family":"Porrello","sequence":"additional","affiliation":[{"name":"Neuromuscular Repair Unit, InSpe and Division of Neuroscience, IRCCS Ospedale San Raffaele , 20132 Milano , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuo","family":"Lin","sequence":"additional","affiliation":[{"name":"Biozentrum, University of Basel , 4056 Basel , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pawel","family":"Pelczar","sequence":"additional","affiliation":[{"name":"Center for Transgenic Models, University of Basel , 4056 Basel , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2546-4357","authenticated-orcid":false,"given":"Stefano C","family":"Previtali","sequence":"additional","affiliation":[{"name":"Neuromuscular Repair Unit, InSpe and Division of Neuroscience, IRCCS Ospedale San Raffaele , 20132 Milano , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4974-9384","authenticated-orcid":false,"given":"Markus A","family":"R\u00fcegg","sequence":"additional","affiliation":[{"name":"Biozentrum, University of Basel , 4056 Basel , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,3,15]]},"reference":[{"issue":"4","key":"2023072815183550000_pgad083-B1","doi-asserted-by":"crossref","first-page":"1651","DOI":"10.1152\/physrev.00048.2011","article-title":"The proprioceptive senses: their roles in signaling body shape, body position and movement, and muscle force","volume":"92","author":"Proske","year":"2012","journal-title":"Physiol Rev"},{"issue":"2","key":"2023072815183550000_pgad083-B2","doi-asserted-by":"crossref","DOI":"10.1101\/cshperspect.a004911","article-title":"Basement 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