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A recent case-only genome-wide association study of CMT1A patients conducted by the Inherited Neuropathy Consortium identified a strong association between strength of foot dorsiflexion and variants in signal induced proliferation associated 1 like 2 (SIPA1L2), indicating that it may be a genetic modifier of disease. To validate SIPA1L2 as a candidate modifier and to assess its potential as a therapeutic target, we engineered mice with deletion of exon 1 (including the start codon) of the Sipa1l2 gene and crossed them to the C3-PMP22 mouse model of CMT1A. Neuromuscular phenotyping showed that Sipa1l2 deletion in C3-PMP22 mice preserved muscular endurance assayed by inverted wire hang duration and changed femoral nerve axon morphometrics such as myelin thickness. Gene expression changes suggest involvement of Sipa1l2 in cholesterol biosynthesis, a pathway that is also implicated in C3-PMP22 mice. Although Sipa1l2 deletion did impact CMT1A-associated phenotypes, thereby validating a genetic interaction, the overall effect on neuropathy was mild.<\/jats:p>","DOI":"10.1093\/jnen\/nlae020","type":"journal-article","created":{"date-parts":[[2024,2,20]],"date-time":"2024-02-20T01:02:11Z","timestamp":1708390931000},"page":"318-330","source":"Crossref","is-referenced-by-count":1,"title":["Testing SIPA1L2 as a modifier of CMT1A using mouse models"],"prefix":"10.1093","volume":"83","author":[{"given":"George C","family":"Murray","sequence":"first","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, Maine, USA"},{"name":"The Graduate School of Biomedical Science and Engineering, The University of Maine , Orono, Maine, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy J","family":"Hines","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, Maine, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abigail L D","family":"Tadenev","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, Maine, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine , Miami, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephan","family":"Z\u00fcchner","sequence":"additional","affiliation":[{"name":"Department of Human Genetics and John P Hussman Institute for Human Genomics, University of Miami Miller School of Medicine , Miami, Florida, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9229-3407","authenticated-orcid":false,"given":"Robert W","family":"Burgess","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, Maine, USA"},{"name":"The Graduate School of 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