{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,20]],"date-time":"2025-10-20T18:48:58Z","timestamp":1760986138336,"version":"3.41.2"},"reference-count":26,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T00:00:00Z","timestamp":1668384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009592","name":"Beijing Municipal Science and Technology Commission","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009592","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Hereditary spastic paraplegias (HSPs) are genetic neurodegenerative diseases. The most common form of pure HSP that is inherited in an autosomal dominant manner is spastic paraplegia type 4 (SPG4), which is caused by mutations in the <jats:italic>SPAST<\/jats:italic> gene. Different theories have been proposed as the mechanism underlying <jats:italic>SPAST<\/jats:italic>-HSP for different types of genetic mutations, including gain- and loss-of-function mechanisms. To better understand the mutation mechanisms, we performed genetic analysis and investigated a truncating <jats:italic>SPAST<\/jats:italic> variant that segregated with disease in one family.<\/jats:p><\/jats:sec><jats:sec><jats:title>Objectives and methods<\/jats:title><jats:p>We described a pure HSP pedigree with family members across four generations. We performed genetic analysis and investigated a novel frameshift pathogenic variant (c.862_863dupAC, p. H289Lfs<jats:sup>*<\/jats:sup>27) in this family. We performed reverse transcription-polymerase chain reaction (RT-PCR), Sanger sequencing, and quantitative RT-PCR using total RNA from an Epstein-Barr virus-induced lymphoblastoid cell line produced from the proband. We also performed Western blotting on cell lysates to investigate if the protein expression of spastin is affected by this variant.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>This variant (c.862_863dupAC, p. H289Lfs<jats:sup>*<\/jats:sup>27) co-segregated with pure HSP in this family and is not registered in any public database. Measurement of <jats:italic>SPAST<\/jats:italic> transcripts in lymphoblasts from the proband demonstrated a reduction of <jats:italic>SPAST<\/jats:italic> transcript levels through likely nonsense-mediated mRNA decay. Immunoblot analyses demonstrated a reduction of spastin protein expression levels in lymphoblasts.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>We report an SPG4 family with a novel heterozygous frameshift variant p.H289Lfs<jats:sup>*<\/jats:sup>27 in <jats:italic>SPAST<\/jats:italic>. Our study implies haploinsufficiency as the pathogenic mechanism for this variant and expands the known mutation spectrum of <jats:italic>SPAST<\/jats:italic>.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fneur.2022.1005544","type":"journal-article","created":{"date-parts":[[2022,11,14]],"date-time":"2022-11-14T14:13:04Z","timestamp":1668435184000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["A novel truncating variant of SPAST associated with hereditary spastic paraplegia indicates a haploinsufficiency pathogenic 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