title: Messenger RNA processing is altered in autosomal dominant leukodystrophy.
abstract: Adult-onset autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurological disorder characterized by autonomic dysfunction, followed by cerebellar and pyramidal features. ADLD is caused by duplication of the lamin B1 gene (LMNB1), which leads to its increased expression. The molecular pathways involved in the disease are still poorly understood. Hence, we analyzed global gene expression in fibroblasts and whole blood of LMNB1 duplication carriers and used Gene Set Enrichment Analysis to explore their gene signatures. We found that LMNB1 duplication is associated with dysregulation of genes involved in the immune system, neuronal and skeletal development. Genes with an altered transcriptional profile clustered in specific genomic regions. Among the dysregulated genes, we further studied the role of RAVER2, which we found to be overexpressed at mRNA and protein level. RAVER2 encodes a putative trans regulator of the splicing repressor polypyrimidine tract binding protein (PTB) and is likely implicated in alternative splicing regulation. Functional studies demonstrated an abnormal splicing pattern of several PTB-target genes and of the myelin protein gene PLP1, previously demonstrated to be involved in ADLD. Mutant mice with different lamin B1 expression levels confirmed that Raver2 expression is dependent on lamin B1 in neural tissue and determines an altered splicing pattern of PTB-target genes and Plp1. Overall our results demonstrate that deregulation of lamin B1 expression induces modified splicing of several genes, likely driven by raver-2 overexpression, and suggest that an alteration of mRNA processing could be a pathogenic mechanism in ADLD.
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna 40123, Italy.
authors: Anna
authors: A
authors: Bartoletti-Stella
authors: Department of Neuroscience and Brain Techonologies, Istituto Italiano di Tecnologia, Genova 16163, Italy.
authors: Laura
authors: L
authors: Gasparini
authors: Department of Neuroscience and Brain Techonologies, Istituto Italiano di Tecnologia, Genova 16163, Italy.
authors: Caterina
authors: C
authors: Giacomini
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna 40123, Italy.
authors: Patrizia
authors: P
authors: Corrado
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna 40123, Italy, IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Ospedale Bellaria, Bologna 40139, Italy.
authors: Rossana
authors: R
authors: Terlizzi
authors: Department of Medical Sciences, University of Torino, Torino 10126, Italy.
authors: Elisa
authors: E
authors: Giorgio
authors: Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna 40138, Italy and.
authors: Pamela
authors: P
authors: Magini
authors: Medical Genetics Unit, Department of Medical and Surgical Sciences, University of Bologna 40138, Italy and.
authors: Marco
authors: M
authors: Seri
authors: IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Ospedale Bellaria, Bologna 40139, Italy.
authors: Agostino
authors: A
authors: Baruzzi
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna 40123, Italy, IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Ospedale Bellaria, Bologna 40139, Italy.
authors: Piero
authors: P
authors: Parchi
authors: Department of Medical Sciences, University of Torino, Torino 10126, Italy, Città della Salute e della Scienza, University Hospital, Medical Genetics Unit, Torino 10126, Italy.
authors: Alfredo
authors: A
authors: Brusco
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna 40123, Italy, IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Ospedale Bellaria, Bologna 40139, Italy.
authors: Pietro
authors: P
authors: Cortelli
authors: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna 40123, Italy, IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Clinica Neurologica, Ospedale Bellaria, Bologna 40139, Italy, sabina.capellari@unibo.it.
authors: Sabina
authors: S
authors: Capellari
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D005347:Fibroblasts / Q000378:metabolism; D020440:Gene Duplication; D020869:Gene Expression Profiling; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics*; D006801:Humans; D034921:Lamin Type B / Q000235:genetics*; D007962:Leukocytes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020371:Pelizaeus-Merzbacher Disease / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D034441:Heterogeneous-Nuclear Ribonucleoproteins; D034921:Lamin Type B; C571037:RAVER2 protein, human
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