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.

Alternative Splicing in the HumanPMP22Gene: Implications in CMT1A Neuropathy

“…6). Of note, in adult-onset autosomal-dominant leukodystrophy and Pelizaeus-Merzbacher disease, two hereditary CNS myelin disorders, alternative splicing of the lamin B1 and PLP1 genes, respectively, is affected [Regis et al, 2009;Bartoletti-Stella et al, 2015]. As these neurological diseases are caused by gene duplication such as CMT1A, we speculate derangement of splicing pattern as an intriguing mechanism to be addressed [Regis et al, 2013].…”

Lamin B1 mediated demyelination: Linking Lamins, Lipids and Leukodystrophies

“…29 Altered mRNA processing has been demonstrated in ADLD fibroblasts and it is thought that this may contribute to an aberrant regulation of myelin specific genes. 30 In conclusion, the recent report by Rolyan et al, (2015) provides evidence that lamin B1 over expression can down regulate the expression of lipid synthesis genes and myelin enriched lipids though age dependent epigenetic pathways. This model provides a mechanistic framework that can, at least partially, explain some aspects of the age dependence and cell type specificity in ADLD.…”

Lamin B1 protein is required for dendrite development in primary mouse cortical neurons

“…We demonstrated that in ADLD human fibroblasts and in the brain of Lmnb1-null ( Lmnb1 Δ/Δ ) mice ( Vergnes et al. , 2004 ), abnormal levels of lamin B1 are associated with imbalanced expression and splicing of genes involved in neuronal development ( Bartoletti-Stella et al. , 2015 ), and lamin B1 finely tunes neuronal versus astrocytic fate commitment during mouse embryonic cortical development (S. Mahajani, C. Giacomini, F. Marinaro, D. DePietri Tonelli, A. Contestabile, and L. Gasparini, unpublished data).…”