{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T02:46:06Z","timestamp":1791859566298,"version":"4.3.4"},"reference-count":16,"publisher":"Springer Science and Business Media LLC","issue":"9","license":[{"start":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T00:00:00Z","timestamp":1775260800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T00:00:00Z","timestamp":1775260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Ministero della Salute","doi-asserted-by":"publisher","award":["Ricerca Corrente 2022-2024"],"award-info":[{"award-number":["Ricerca Corrente 2022-2024"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Neurol Sci"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Mutations in progranulin gene (\n                      <jats:italic>GRN<\/jats:italic>\n                      ) are a major cause of frontotemporal dementia (FTD). Most reported pathogenic mutations are nonsense, frameshift, or splicing mutations, resulting in a premature stop codon, degradation of mutated mRNA and consequent protein haploinsufficiency.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>\n                      In this study, we analysed four subjects with FTD who had low plasma progranulin levels but no mutation detectable by sequencing of\n                      <jats:italic>GRN<\/jats:italic>\n                      , to disclose the underlying genetic cause of disease.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Multiplex ligation-dependent probe amplification (MLPA) method was applied to search for rearrangements in\n                      <jats:italic>GRN<\/jats:italic>\n                      . Region-specific polymerase chain reaction (PCR) and Sanger sequencing were performed to define the breakpoint. Quantitative real-time PCR (qRT-PCR) on\n                      <jats:italic>GRN<\/jats:italic>\n                      mRNA and haplotype sharing analysis were also performed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      MLPA revealed in all the subjects the same heterozygous deletion, and a possible common ancestor was suggested by haplotype sharing. PCR and sequencing allowed us to define the size of the deletion (3028\u00a0bp), that removes part of\n                      <jats:italic>GRN<\/jats:italic>\n                      promoter, exon 1 including the transcription start site and most of the intron 1, and the breakpoints. qRT-PCR showed reduced level of mRNA, confirming the pathological nature of the deletion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      In this study, we described a\n                      <jats:italic>GRN<\/jats:italic>\n                      heterozygous gross deletion which removes the consensus sequences for transcription factors and the transcription start site, leading to a reduced levels of plasma progranulin. Our study indicates that\n                      <jats:italic>GRN<\/jats:italic>\n                      rearrangements, although not common, should be investigated in patients with FTD who show low plasma progranulin levels but no\n                      <jats:italic>GRN<\/jats:italic>\n                      mutations detectable by DNA sequencing.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10072-026-09030-3","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T03:37:45Z","timestamp":1785987465000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A novel gross deletion in the progranulin gene in four subjects with frontotemporal dementia"],"prefix":"10.1007","volume":"47","author":[{"given":"M.","family":"Ricci","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G.","family":"Di Fede","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Caroppo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V.","family":"Aprea","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C.","family":"Villa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Romeo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Tiraboschi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A.","family":"Marti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Grisoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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